Manufacture of variable density dosage forms utilizing radiofrequency energy

ABSTRACT

The present invention features the present invention features a tablet including at least one pharmaceutically active ingredient, wherein the shape of said tablet includes at least one major face wherein: (i) the peak penetration resistance at the perimeter of said major face of the tablet is at least about 10% greater than the peak penetration resistance at the center of said major face; and (ii) the tablet disintegrates in the mouth when placed on the tongue in less than about 30 seconds, and a machine and method for manufacture of such tablet.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 12/887,544, filed Sep. 22, 2010, U.S. patent application Ser.No. 12/887,569, filed Sep. 22, 2010, and U.S. patent application Ser.No. 12/887,552, filed Sep. 22, 2010, all of which are currently pendingand all of which claim priority to U.S. Provisional Application Ser. No.61/245,315, filed Sep. 24, 2009, U.S. Provisional Application Ser. No.61/255,582, filed Oct. 28, 2009, U.S. Provisional Application Ser. No.61/314,629, filed Mar. 17, 2010, and U.S. Provisional Application Ser.No. 61/358,167, filed Jun. 24, 2010. The complete disclosures of theaforementioned related U.S. patent applications are hereby incorporatedherein by reference for all purposes.

BACKGROUND OF THE INVENTION

Pharmaceuticals intended for oral administration are typically providedin tablet form. Tablets are swallowed whole, chewed in the mouth, ordisintegrated in the oral cavity. Soft tablets that either are chewed ordissolve in the mouth are often employed in the administration ofpharmaceuticals where it is impractical to provide a tablet forswallowing whole. With chewable tablets, the act of chewing helps tobreak up the tablet particles as the tablet disintegrates and mayincrease the rate of absorption by the digestive tract. Soft tablets arealso advantageous where it is desirable to make a pharmaceuticallyactive agent available topically in the mouth or throat for both localeffects and/or systemic absorption. Soft tablets are also utilized toimprove drug administration in pediatric and geriatric patients. Softtablets designed to disintegrate in the mouth prior to swallowing areparticularly useful for improving compliance of pediatric patients.

Generally, soft tablets are made by compaction of a blend of powderedingredients and typically include a pharmaceutically active agent,flavoring, and/or binders. The powder blend is typically fed into thecavity of a die of a tablet press and a tablet is formed by applyingpressure. Hardness of the resulting tablet is a direct function of thecompaction pressure employed and the compatibility of the ingredients inthe formulation. A softer tablet, having an easier bite-through, may beprepared by employing reduced compaction pressures. The resulting tabletis softer, but also more fragile, brittle, and easily chipped anddisadvantageously can involve complex and costly processing steps.Examples of soft tablets designed to disintegrate in the mouth withoutchewing are disclosed in U.S. Pat. Nos. 5,464,632, 5,223,264, 5,178,878,6,589,554, and 6,224,905.

There is a need for aesthetically pleasing chewable and orallydisintegrating tablets that utilizes compression-based tabletingmachines typically used to produce high density, hard swallowabletablets. When used at low compression forces, these machines typicallyproduce highly friable tablets, which are not sufficiently stable duringpackaging, shipping, and storage. The present invention relates to thediscovery of a machine and a process for making dosage forms, such aschewable or orally disintegrating tablets, using radiofrequency energy(“RF energy”). Further, the present invention relates to the discoveryof the manufacture of such a dosage form having varying levels ofhardness and thickness, thereby able to deliver a unique consumerexperience

SUMMARY OF THE INVENTION

In one aspect, the present invention features a machine for theproduction of a solid dosage form (e.g., a tablet) including: (a) a dieplaten having one or more forming cavities each having an inner wall, afirst opening at the surface of one side of the die platen, and a secondopening at the surface on the opposite side of the die platen; (b) oneor more first forming tools each adapted to move into one of the formingcavities through the first opening of the forming cavity; (c) one ormore second forming tools each adapted to move adjacent to one of thesecond openings or into one of the forming cavities through the secondopening of the forming cavity; (d) at least one first RF electrodeoperably associated with the one or more first forming tools, the one ormore second forming tools, or the inner wall of the one or more formingcavities; and (e) at least one second RF electrode operably associatedwith the one or more first forming tools, the one or more second formingtools, or the inner wall of the one or more forming cavities; whereinthe machine is adapted to form a dosage form between a first formingtool and a second forming tool within a forming cavity and wherein thefirst RF electrode and the second RF electrode are arranged within themachine such that when RF energy is conducted between the first RFelectrode and the second RF electrode, the RF energy passes through theportion of the forming cavity adapted to form the dosage form. Examplesof solid dosage forms include tablets (e.g., swallowable, chewable, andorally disintegrating tablets), gums, and lozenges.

The present invention also features a method of making a dosage formusing such a machine by: (a) adding a powder blend to a forming cavity;(b) moving a first forming tool into the forming cavity through thefirst opening of the forming cavity such that the powder blend is formedinto the shape of the dosage form within the forming cavity between thefirst forming tool and a second forming tool; (c) conducting RF energybetween the first electrode and the second electrode such that theenergy heats the powder blend within the forming cavity to form thedosage form; and (d) removing the dosage form from the forming cavity.

In another aspect, the present invention features a machine for theproduction of a solid dosage form, the machine including: (a) a dieplaten having one or more forming cavities each having an inner wall, afirst opening at the surface of one side of the die platen, and a secondopening at the surface on the opposite side of the die platen; (b) oneor more first forming tools having a dosage form contacting firstsurface, each of the one or more first forming tools adapted to moveinto one of the cavities through the first opening of the formingcavity; (c) one or more second forming tools having a dosage formcontacting second surface, each of the one or more second forming toolsadapted to move into one of the cavities through the second opening ofthe forming cavity; (d) at least one first RF electrode operablyassociated with the one or more first forming tools, the one or moresecond forming tools, or the inner wall of the one or more formingcavities; and (e) at least one second RF electrode operably associatedwith the one or more first forming tools, the one or more second formingtools, or the inner wall of the one or more forming cavities; wherein atleast a portion of the dosage form contacting first surface and/or atleast a portion of the dosage form contacting second surface is movableand wherein the machine is adapted to form a dosage form between thedosage form contacting first surface and the dosage form contactingsecond surface within a forming cavity and wherein the first RFelectrode and the second RF electrode are arranged within the machinesuch that when RF energy is conducted between the first RF electrode andthe second RF electrode, the RF energy passes through the portion of theforming cavity adapted to form the dosage form.

In another aspect, the present invention features a method of making asolid dosage form using such a machine, the method including the stepsof: (a) adding a powder blend to a forming cavity; (b) moving a firstforming tool into the forming cavity through the first opening of theforming cavity such that the powder blend is formed into the shape ofthe dosage form within the forming cavity between the dosage formcontacting first surface and the dosage form contacting second surface;(c) conducting RF energy between the first electrode and the secondelectrode such that the energy heats the powder blend within the formingcavity to form the dosage form; and (d) removing the dosage form fromthe forming cavity.

In another aspect, the present invention features a tablet including atleast one pharmaceutically active ingredient, wherein the shape of saidtablet includes at least one major face wherein: (i) the peakpenetration resistance at the perimeter of said major face of the tabletis at least about 10% greater than the peak penetration resistance atthe center of said major face; and (ii) the tablet disintegrates in themouth when placed on the tongue in less than about 30 seconds.

In another aspect, the present invention features a tablet including atleast one pharmaceutically active ingredient, wherein the shape of saidtablet includes at least one major face wherein: (i) the peakpenetration resistance at the center of said major face is less than 250grams and (ii) the tablet disintegrates in the mouth when placed on thetongue in less than about 30 seconds.

Other features and advantages of the present invention will be apparentfrom the detailed description of the invention and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-F are cross-section, side views of an embodiment of theinvention showing the manufacture of tablet 4 a from powder blend 4within die platen 2.

FIGS. 2A-H are cross-section, side views of an embodiment of theinvention showing the manufacture of a bilayer tablet 12 from powderblends 10 and 11 within die platen 2.

FIGS. 3A-G are cross-section, side views of an embodiment of theinvention showing the manufacture of tablet 40 containing preformedinserts 30 and 31 from powder blend 20 within die platen 2.

FIGS. 4A and 4B are a perspective view of a rotary indexing machine 195.

FIGS. 5A and 5B are top views of the rotary indexing machine 195 in thedwell position.

FIGS. 6A and 6B are section views of the lower forming tool assembly 110in the start position of the manufacturing cycle.

FIG. 7 is a section view through the RF station rotary indexing machine195 prior to compacting powder blend 101.

FIG. 8 is a section view through the RF station rotary indexing machine195 prior showing the manufacture of tablets 101 a.

FIG. 9 is a section view through tablet ejection station 160 beforetablets 101 a have been ejected.

FIG. 10 is a section view through tablet ejection station 160 aftertablets 101 a have been ejected into blister 190.

FIGS. 11A-F are cross sections of alternate embodiments of forming toolsand the die platen.

FIGS. 12A-D are cross sections of alternate embodiments of forming toolsand the die platen.

FIG. 13A is a cross section of forming tools having a wave-shapedsurface.

FIG. 13B is a perspective view of forming tools having a wave-shapedsurface.

FIG. 14 is a cross section of forming tools having protrusions at thesurface.

FIG. 15A is a cross section of forming tools having a contacting surfacethat are movable.

FIG. 15B is a perspective of forming tools having a contacting surfacethat are movable and the resulting tablet having a major face withvarious average peak penetration resistances.

FIG. 16 is a cross section of forming tools that contain a spring.

DETAILED DESCRIPTION OF THE INVENTION

It is believed that one skilled in the art can, based upon thedescription herein, utilize the present invention to its fullest extent.The following specific embodiments can be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention belongs. Also, all publications, patentapplications, patents, and other references mentioned herein areincorporated by reference. As used herein, all percentages are by weightunless otherwise specified.

As discussed above, in one aspect, the present invention features amethod of making a dosage form using such a machine by: (a) adding apowder blend to a forming cavity; (b) moving a first forming tool intothe forming cavity through the first opening of the forming cavity suchthat the powder blend is formed into the shape of the dosage form withinthe forming cavity between the first forming tool and a second formingtool; (c) conducting RF energy between the first electrode and thesecond electrode such that the energy heats the powder blend within theforming cavity to form the dosage form; and (d) removing the dosage formfrom the forming cavity. While the specific embodiments herein focus ontablets, other dosage forms such as lozenges and chewing gums can alsobe made by such machine and process.

Powder Blend

As discussed above, the tablet is manufactured by compacting a powderblend containing a pharmaceutically active agent (as discussed herein),a meltable binder (as discussed herein), and optionally apharmaceutically-acceptable carrier. The carrier contains one or moresuitable excipients for the formulation of tablets. Examples of suitableexcipients include, but are not limited to, fillers, adsorbents,disintegrants, lubricants, glidants, sweeteners, superdisintegrants,flavor and aroma agents, antioxidants, preservatives, texture enhancers,and mixtures thereof. One or more of the above ingredients may bepresent on the same particle of the powder blend.

Suitable fillers include, but are not limited to, carbohydrates (asdiscussed herein) and water insoluble plastically deforming materials(e.g., microcrystalline cellulose or other cellulosic derivatives), andmixtures thereof.

Suitable adsorbents include, but are not limited to, water-insolubleadsorbents such as dicalcium phosphate, tricalcium phosphate, silicifiedmicrocrystalline cellulose (e.g., such as distributed under the PROSOLVbrand (PenWest Pharmaceuticals, Patterson, N.Y.)), magnesiumaluminometasilicate (e.g., such as distributed under the to NEUSILINbrand (Fuji Chemical Industries (USA) Inc., Robbinsville, N.J.)), clays,silicas, bentonite, zeolites, magnesium silicates, hydrotalcite, veegum,and mixtures thereof.

Suitable disintegrants include, but are not limited to, sodium starchglycolate, cross-linked polyvinylpyrrolidone, cross-linkedcarboxymethylcellulose, starches, microcrystalline cellulose, andmixtures thereof.

Suitable lubricants include, but are not limited to, long chain fattyacids and their salts, such as magnesium stearate and stearic acid,talc, glycerides waxes, and mixtures thereof.

Suitable glidants include, but are not limited to, colloidal silicondioxide.

Examples of sweeteners include, but are not limited to, synthetic ornatural sugars; artificial sweeteners such as saccharin, sodiumsaccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose,dihydrochalcone, alitame, miraculin, monellin, and stevside; sugaralcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol, andxylitol; sugars extracted from sugar cane and sugar beet (sucrose),dextrose (also called glucose), fructose (also called laevulose), andlactose (also called milk sugar); isomalt, salts thereof, and mixturesthereof.

Examples of superdisintegrants include, but are not limited to,croscarmellose sodium, sodium starch glycolate and cross-linked povidone(crospovidone). In one embodiment the tablet contains up to about 5% byweight of such superdisintegrant.

Examples of flavors and aromatics include, but are not limited to,essential oils including distillations, solvent extractions, or coldexpressions of chopped flowers, leaves, peel or pulped whole fruitcontaining mixtures of alcohols, esters, aldehydes and lactones;essences including either diluted solutions of essential oils, ormixtures of synthetic chemicals blended to match the natural flavor ofthe fruit (e.g., strawberry, raspberry and black currant); artificialand natural flavors of brews and liquors, e.g., cognac, whisky, rum,gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint;fruit juices including expelled juice from washed, scrubbed fruits suchas lemon, orange, and lime; spear mint, pepper mint, wintergreen,cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseedsnuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts),almonds, raisins; and powder, flour, or vegetable material partsincluding tobacco plant parts, e.g., genus Nicotiana, in amounts notcontributing significantly to the level of nicotine, and ginger.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.

Examples of preservatives include, but are not limited to, citric acid,tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, andsorbic acid, and mixtures thereof.

Examples of texture enhancers include, but are not limited to, pectin,polyethylene oxide, and carrageenan, and mixtures thereof. In oneembodiment, texture enhancers are used at levels of from about 0.1% toabout 10% percent by weight.

In one embodiment of the invention, the powder blend has an averageparticle size of less than 500 microns, such as from about 50 microns toabout 500 microns, such as from about 50 microns and 300 microns.Particles in this size range are particularly useful for directcompacting processes.

In one embodiment of the invention, the tablet may be a made from apowder blend that is substantially free of hydrated polymers. As usedherein, what is meant by “substantially free” is less than 5%, such asless than 1%, such as less than 0.1%, such as completely free (e.g.,0%). Such a composition is advantageous for maintaining an immediaterelease dissolution profile, minimizing processing and material costs,and providing for optimal physical and chemical stability of the tablet.

In one embodiment, powder blend/tablet is substantially free of directlycompressible water insoluble fillers. Water insoluble fillers includebut are not limited to microcrystalline cellulose, directly compressiblemicrocrystalline cellulose, celluloses, water insoluble celluloses,starch, cornstarch and modified starches. As described in thisembodiment, substantially free is less than 2 percent, e.g. less than 1percent or none.

Meltable Binder

The powder blend/tablet of the present invention includes at least onemeltable binder. In one embodiment, the meltable binder has a meltingpoint of from about 40° C. to about 140° C., such as from about 55° C.to about 100° C. The softening or melting of the meltable binder(s)results in the sintering of the tablet shape through the binding of thesoftened or melted binder with the pharmaceutically active agent and/orother ingredients within the compacted powder blend.

In one embodiment, the meltable binder is a RF-meltable binder. What ismeant by an RF-meltable binder is a solid binder that can be softened ormelted upon exposure to RF energy. The RF-meltable binder typically ispolar and has the capability to re-harden or resolidify upon cooling.

In one embodiment, the meltable binder is not a RF-meltable binder. Insuch embodiment, the powder blend contains an excipient that heats uponexposure to RF energy (e.g., a polar excipient), such that the resultingheat from is able to soften or melt the meltable binder. Examples ofsuch excipients include, but are not limited to, polar liquids such aswater and glycerin; powdered metals and metal salts such as powderediron, sodium chloride, aluminum hydroxide, and magnesium hydroxide;stearic acid; maltodextrin and sodium stearate.

Other examples of meltable binders include amorphous carbohydratepolymers. What is meant by an “amorphous carbohydrate polymer” is amolecule having a plurality of carbohydrate monomers wherein suchmolecule has a crystallinity of less than 20%, such as less than 10%,such as less than 5%. Examples of amorphous carbohydrate polymersinclude, but are not limited to hydrogenated starch hydrosolate,polydextrose, and oligosaccharides. Examples of oligosaccharidesinclude, but are not limited to, fructo-oligosaccharide,galacto-oligosaccharide malto-oligosaccharide, inulin, andisolmalto-oligosaccharide

Examples of suitable meltable binders include: fats such as cocoabutter, hydrogenated vegetable oil such as palm kernel oil, cottonseedoil, sunflower oil, and soybean oil; mono, di, and triglycerides;phospholipids; cetyl alcohol; waxes such as Carnauba wax, spermacetiwax, beeswax, candelilla wax, shellac wax, microcrystalline wax, andparaffin wax; water soluble polymers such as polyethylene glycol,polycaprolactone, GlycoWax-932, lauroyl macrogol-32 glycerides, andstearoyl macrogol-32 glycerides; polyethylene oxides; and sucroseesters.

In one embodiment, the meltable binder is a RF-meltable binder, and theRF-meltable binder is a polyethylene glycol (PEG), such as PEG-4000. Aparticularly preferred RF-meltable binder is PEG having at least 95% byweight of the PEG particles less than 100 microns (as measured byconventional means such as light or laser scattering or sieve analysis)and a molecular weight between 3000 and 8000 Daltons.

The meltable binder(s) may be present at level of about 0.01 percent toabout 70 percent of the powder blend/tablet, such as from about 1percent to about 50 percent, such as from about 10 percent to about 30percent of the powder blend/tablet. In one embodiment, the averageparticle size of the binder is less than 250 microns, such as less than100 microns.

Carbohydrate

In one embodiment, the powder blend contains at least one carbohydrate.The carbohydrate can contribute to the dissolvability and mouth feel ofthe tablet, aid in distributing the meltable binder across a broadersurface area, and diluting and cushioning the pharmaceutically activeagent. Examples of carbohydrates include, but are not limited to,water-soluble compressible carbohydrates such as sugars (e.g., dextrose,sucrose, maltose, isomalt, and lactose), starches (e.g., corn starch),sugar-alcohols (e.g., mannitol, sorbitol, maltitol, erythritol,lactitol, and xylitol), and starch hydrolysates (e.g., dextrins, andmaltodextrins).

The carbohydrate(s) may be present at level of about 5 percent to about95 percent of the powder blend/tablet, such as from about 20 percent toabout 90 percent or from about 40 percent to about 80 percent of thepowder blend/tablet. The particle size of the of carbohydrate caninfluence the level of meltable binder used, wherein a higher particlesize of carbohydrate provides a lower surface area and subsequentlyrequires a lower level of meltable binder. In one embodiment, whereinthe carbohydrate(s) is greater than 50% by weight of the powder blendand the mean particle size of the carbohydrate(s) is greater than 100microns, then the meltable binder is from about 10 to about 30 percentby weight of the powder blend/tablet.

Pharmaceutically Active Agent

The powder blend/tablet of the present invention includes at least onepharmaceutically active agent. What is meant by a “pharmaceuticallyactive agent” is an agent (e.g., a compound) that is permitted orapproved by the U.S. Food and Drug Administration, European MedicinesAgency, or any successor entity thereof, for the oral treatment of acondition or disease. Suitable pharmaceutically active agents include,but are not limited to, analgesics, anti-inflammatory agents,antipyretics, antihistamines, antibiotics (e.g., antibacterial,antiviral, and antifungal agents), antidepressants, antidiabetic agents,antispasmodics, appetite suppressants, bronchodilators, cardiovasculartreating agents (e.g., statins), central nervous system treating agents,cough suppressants, decongestants, diuretics, expectorants,gastrointestinal treating agents, anesthetics, mucolytics, musclerelaxants, osteoporosis treating agents, stimulants, nicotine, andsedatives.

Examples of suitable gastrointestinal treating agents include, but arenot limited to: antacids such as aluminum-containing pharmaceuticallyactive agents (e.g., aluminum carbonate, aluminum hydroxide,dihydroxyaluminum sodium carbonate, and aluminum phosphate),bicarbonate-containing pharmaceutically active agents,bismuth-containing pharmaceutically active agents (e.g., bismuthaluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate,and bismuth subnitrate), calcium-containing pharmaceutically activeagents (e.g., calcium carbonate), glycine, magnesium-containingpharmaceutically active agents (e.g., magaldrate, magnesiumaluminosilicates, magnesium carbonate, magnesium glycinate, magnesiumhydroxide, magnesium oxide, and magnesium trisilicate),phosphate-containing pharmaceutically active agents (e.g., aluminumphosphate and calcium phosphate), potassium-containing pharmaceuticallyactive agents (e.g., potassium bicarbonate), sodium-containingpharmaceutically active agents (e.g., sodium bicarbonate), andsilicates; laxatives such as stool softeners (e.g., docusate) andstimulant laxatives (e.g., bisacodyl); H2 receptor antagonists, such asfamotidine, ranitidine, cimetadine, and nizatidine; proton pumpinhibitors such as omeprazole, dextansoprazole, esomeprazole,pantoprazole, rabeprazole, and lansoprazole; gastrointestinalcytoprotectives, such as sucraflate and misoprostol; gastrointestinalprokinetics such as prucalopride; antibiotics for H. pylori, such asclarithromycin, amoxicillin, tetracycline, and metronidazole;antidiarrheals, such as bismuth subsalicylate, kaolin, diphenoxylate,and loperamide; glycopyrrolate; analgesics, such as mesalamine;antiemetics such as ondansetron, cyclizine, diphenyhydroamine,dimenhydrinate, meclizine, promethazine, and hydroxyzine; probioticbacteria including but not limited to lactobacilli; lactase;racecadotril; and antiflatulents such as polydimethylsiloxanes (e.g.,dimethicone and simethicone, including those disclosed in U.S. Pat. Nos.4,906,478, 5,275,822, and 6,103,260); isomers thereof; andpharmaceutically acceptable salts and prodrugs (e.g., esters) thereof.

Examples of suitable analgesics, anti-inflammatories, and antipyreticsinclude, but are not limited to, non-steroidal anti-inflammatory drugs(NSAIDs) such as propionic acid derivatives (e.g., ibuprofen, naproxen,ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen,fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, and suprofen)and COX inhibitors such as celecoxib; acetaminophen; acetyl salicylicacid; acetic acid derivatives such as indomethacin, diclofenac,sulindac, and tolmetin; fenamic acid derivatives such as mefanamic acid,meclofenamic acid, and flufenamic acid; biphenylcarbodylic acidderivatives such as diflunisal and flufenisal; and oxicams such aspiroxicam, sudoxicam, isoxicam, and meloxicam; isomers thereof; andpharmaceutically acceptable salts and prodrugs thereof.

Examples of antihistamines and decongestants, include, but are notlimited to, bromopheniramine, chlorcyclizine, dexbrompheniramine,bromhexane, phenindamine, pheniramine, pyrilamine, thonzylamine,pripolidine, ephedrine, phenylephrine, pseudoephedrine,phenylpropanolamine, chlorpheniramine, dextromethorphan,diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine,naphazoline, oxymetazoline, montelukast, propylhexadrine, triprolidine,clemastine, acrivastine, promethazine, oxomemazine, mequitazine,buclizine, bromhexine, ketotifen, terfenadine, ebastine, oxatamide,xylomeazoline, loratadine, desloratadine, and cetirizine; isomersthereof; and pharmaceutically acceptable salts and esters thereof.

Examples of cough suppressants and expectorants include, but are notlimited to, diphenhydramine, dextromethorphan, noscapine, clophedianol,menthol, benzonatate, ethylmorphone, codeine, acetylcysteine,carbocisteine, ambroxol, belladona alkaloids, sobrenol, guaiacol, andguaifenesin; isomers thereof; and pharmaceutically acceptable salts andprodrugs thereof.

Examples of muscle relaxants include, but are not limited to,cyclobenzaprine and chlorzoxazone metaxalone, orphenadrine, andmethocarbamol; isomers thereof; and pharmaceutically acceptable saltsand prodrugs thereof.

Examples of stimulants include, but are not limited to, caffeine.

Examples of sedatives include, but are not limited to sleep aids such asantihistamines (e.g., diphenhydramine), eszopiclone, and zolpidem, andpharmaceutically acceptable salts and prodrugs thereof.

Examples of appetite suppressants include, but are not limited to,phenylpropanolamine, phentermine, and diethylcathinone, andpharmaceutically acceptable salts and prodrugs thereof.

Examples of anesthetics (e.g., for the treatment of sore throat)include, but are not limited to dyclonine, benzocaine, and pectin andpharmaceutically acceptable salts and prodrugs thereof.

Examples of suitable statins include but are not limited to atorvastin,rosuvastatin, fluvastatin, lovastatin, simvustatin, atorvastatin,pravastatin and pharmaceutically acceptable salts and prodrugs thereof.

In one embodiment, the pharmaceutically active agent included within thetablet is selected from phenylephrine, dextromethorphan,pseudoephedrine, acetaminophen, cetirizine, aspirin, nicotine,ranitidine, ibuprofen, ketoprofen, loperamide, famotidine, calciumcarbonate, simethicone, chlorpheniramine, methocarbomal, chlophedianol,ascorbic acid, pectin, dyclonine, benzocaine and menthol, andpharmaceutically acceptable salts and prodrugs thereof.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of pharmaceutically acceptablesalts, such as acidic/anionic or basic/cationic salts. Pharmaceuticallyacceptable acidic/anionic salts include, and are not limited to acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphospate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate and triethiodide. Pharmaceutically acceptablebasic/cationic salts include, and are not limited to aluminum,benzathine, calcium, chloroprocaine, choline, diethanolamine,ethylenediamine, lithium, magnesium, meglumine, potassium, procaine,sodium and zinc.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of prodrugs of thepharmaceutically active agents. In general, such prodrugs will befunctional derivatives of the pharmaceutically active agent, which arereadily convertible in vivo into the required pharmaceutically activeagent. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985. In addition to salts, theinvention provides the esters, amides, and other protected orderivatized forms of the described compounds.

Where the pharmaceutically active agents according to this inventionhave at least one chiral center, they may accordingly exist asenantiomers. Where the pharmaceutically active agents possess two ormore chiral centers, they may additionally exist as diastereomers. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention. Furthermore, someof the crystalline forms for the pharmaceutically active agents mayexist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the pharmaceutically activeagents may form solvates with water (e.g., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention.

In one embodiment, the pharmaceutically active agent or agents arepresent in the tablet in a therapeutically effective amount, which is anamount that produces the desired therapeutic response upon oraladministration and can be readily determined by one skilled in the art.In determining such amounts, the particular pharmaceutically activeagent being administered, the bioavailability characteristics of thepharmaceutically active agent, the dose regime, the age and weight ofthe patient, and other factors must be considered, as known in the art.

The pharmaceutically active agent may be present in various forms. Forexample, the pharmaceutically active agent may be dispersed at themolecular level, e.g. melted, within the tablet, or may be in the formof particles, which in turn may be coated or uncoated. If thepharmaceutically active agent is in form of particles, the particles(whether coated or uncoated) typically have an average particle size offrom about 1 to about 2000 microns. In one embodiment, such particlesare crystals having an average particle size of from about 1 to about300 microns. In another embodiment, the particles are granules orpellets having an average particle size of from about 50 to about 2000microns, such as from about 50 to about 1000 microns, such as from about100 to about 800 microns.

The pharmaceutically active agent may be present in pure crystal form orin a granulated form prior to the addition of the taste masking coating.Granulation techniques may be used to improve the flow characteristicsor particle size of the pharmaceutically active agents to make it moresuitable for compaction or subsequent coating. Suitable binders formaking the granulation include but are not limited to starch,polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose,and hydroxypropylcellulose. The particles including pharmaceuticallyactive agent(s) may be made by cogranulating the pharmaceutically activeagent(s) with suitable substrate particles via any of the granulationmethods known in the art. Examples of such granulation method include,but are not limited to, high sheer wet granulation and fluid bedgranulation such as rotary fluid bed granulation.

If the pharmaceutically active agent has an objectionable taste, thepharmaceutically active agent may be coated with a taste maskingcoating, as known in the art. Examples of suitable taste maskingcoatings are described in U.S. Pat. No. 4,851,226, U.S. Pat. No.5,075,114, and U.S. Pat. No. 5,489,436. Commercially available tastemasked pharmaceutically active agents may also be employed. For example,acetaminophen particles, which are encapsulated with ethylcellulose orother polymers by a coacervation process, may be used in the presentinvention. Coacervation-encapsulated acetaminophen may be purchasedcommercially from Eurand America, Inc. (Vandalia, Ohio) or from CircaInc. (Dayton, Ohio).

In one embodiment, the tablet incorporates modified release coatedparticles (e.g., particles containing at least one pharmaceuticallyactive agent that convey modified release properties of such agent). Asused herein, “modified release” shall apply to the altered release ordissolution of the active agent in a dissolution medium, such asgastrointestinal fluids. Types of modified release include, but are notlimited to, sustained release or delayed release. In general, modifiedrelease tablets are formulated to make the active agents(s) availableover an extended period of time after ingestion, which thereby allowsfor a reduction in dosing frequency compared to the dosing of the sameactive agent(s) in a conventional tablet. Modified release tablets alsopermit the use of active agent combinations wherein the duration of onepharmaceutically active agent may differ from the duration of anotherpharmaceutically active agent. In one embodiment the tablet contains onepharmaceutically active agent that is released in an immediate releasemanner and an additional active agent or a second portion of the sameactive agent as the first that is modified release.

Examples of swellable, erodible hydrophilic materials for use as arelease modifying excipient for use in the modified release coatinginclude water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, and gelling starches. Examples of water swellable cellulosederivatives include sodium carboxymethylcellulose, cross-linkedhydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose. Examplesof polyalkylene glycols include polyethylene glycol. Examples ofsuitable thermoplastic polyalkylene oxides include poly (ethyleneoxide). Examples of acrylic polymers include potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate, andhigh-molecular weight cross-linked acrylic acid homopolymers andcopolymers.

Suitable pH-dependent polymers for use as release-modifying excipientsfor use in the modified release coating include: enteric cellulosederivatives such as hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, and cellulose acetatephthalate; natural resins such as shellac and zein; enteric acetatederivatives such as polyvinylacetate phthalate, cellulose acetatephthalate, and acetaldehyde dimethylcellulose acetate; and entericacrylate derivatives such as for example polymethacrylate-based polymerssuch as poly(methacrylic acid, methyl methacrylate) 1:2 (available fromRohm Pharma GmbH under the tradename EUDRAGIT S) and poly(methacrylicacid, methyl methacrylate) 1:1 (available from Rohm Pharma GmbH underthe tradename EUDRAGIT L).

In one embodiment the pharmaceutically active agent is coated with acombination of a water insoluble film forming polymer (such as but notlimited to cellulose acetate or ethylcellulose) and a water solublepolymer (such as but not limited to povidone, polymethacrylicco-polymers such as those sold under the tradename Eudragit E-100 fromRohm America, and hydroxypropylcellulose). In this embodiment, the ratioof water insoluble film forming polymer to water soluble polymer is fromabout 50 to about 95 percent of water insoluble polymer and from about 5to about 50 percent of water soluble polymer, and the weight percent ofthe coating by weight of the coated taste-masked particle is from about5 percent to about 40 percent. In one embodiment, the coating which isused in the coated particle of the pharmaceutically active agent issubstantially free of a material (such as polyethylene glycol) whichmelts below 85° C., in order to prevent damage to the integrity of thecoating during the RF heating step.

In one embodiment, one or more pharmaceutically active agents or aportion of the pharmaceutically active agent may be bound to an ionexchange resin for the purposes of taste-masking the pharmaceuticallyactive agent or delivering the active in a modified release manner.

In one embodiment, the pharmaceutically active agent is capable ofdissolution upon contact with a fluid such as water, stomach acid,intestinal fluid or the like. In one embodiment, the dissolutioncharacteristics of the pharmaceutically active agent within the tabletmeets USP specifications for immediate release tablets including thepharmaceutically active agent. For example, for acetaminophen tablets,USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2(paddles) at 50 rpm, at least 80% of the acetaminophen contained in thetablet is released there from within 30 minutes after dosing, and foribuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer,using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofencontained in the tablet is released there from within 60 minutes afterdosing. See USP 24, 2000 Version, 19-20 and 856 (1999). In anotherembodiment, the dissolution characteristics of the pharmaceuticallyactive agent are modified: e.g. controlled, sustained, extended,retarded, prolonged, delayed and the like.

In one embodiment, the particle size of the pharmaceutically activeagent causes more void spaces to be present in the tablet, wherein ahigher particle size of the pharmaceutically active agent subsequentlyrequires a lower level of meltable binder. In one embodiment, whereinthe pharmaceutically active agent or coated pharmaceutically activeagent(s) is greater than 50% of the blend by weight of the powderblend/tablet and the mean particle size of the carbohydrate is greaterthan 100 microns, the meltable binder is from about 10 to about 30percent by weight of the powder blend/tablet. In one embodiment, whereinthe mean particle size of the powder blend is between about 100 micronsand about 300 microns, then meltable binder is from about 10 to about 20percent by weight of the powder blend/tablet.

The melting point of the pharmaceutically active agent can have animpact on the temperature used during the heating step and the type ofmeltable binder used. In one embodiment, the melting point of themeltable binder is less than the melting point of the pharmaceuticallyactive agent. In another embodiment, the melting point of thepharmaceutically active agent is the same or lower than the meltingpoint of the meltable binder, in which case during the fusing or heatingstep, both the pharmaceutically active agent and the meltable binder maymelt and create a eutectic or various bridges of the pharmaceuticallyactive agent and meltable binder between the other materials in thetablet form upon cooling. In one embodiment, the heating temperature isabove the melting point of the meltable binder and below the meltingpoint of the pharmaceutically active agent. In one embodiment whereinibuprofen is the pharmaceutically active agent, the meltable binder isheated from about 30° C. to about 60° C. In one embodiment, thepharmaceutically active agent is the meltable binder.

In one embodiment, the pharmaceutically active agent is in the form of aparticle that is coated with the meltable binder.

The susceptibility to RF energy of the pharmaceutically active agent(e.g., to melt or degrade) can have an impact on the type of energyand/or temperature used during the heating step as well as the type ofthe meltable binder used.

In one embodiment, the processing of the tablet is free of a wet or hotmelt granulation step. In this embodiment, the materials are directlyblended prior to the addition of heat. In one embodiment, the materialsare directly blended and compressed prior to the addition of heat.

Manufacture of Tablet Shape

In one embodiment, the powder blend is fed into the tablet die of anapparatus that applies pressure to form the tablet shape (e.g., by lightcompaction such as tamping). Any suitable compacting apparatus may beused, including, but not limited to, a conventional unitary or rotarytablet press. In one embodiment, the tablet shape may be formed bycompaction using a rotary tablet press (e.g., such as those commerciallyavailable from Fette America Inc., Rockaway, N.J. or Manesty MachinesLTD, Liverpool, UK). In one embodiment, the tablet shape is heated afterit is removed from the tablet press. In another embodiment, the tabletshape is heated within the tablet press.

In one embodiment, to obtain desired attribute of an orallydisintegrating tablet, the tablet's construction may be highly porous,use a minimal amount of binder, and/or have a low density. Such tablets,therefore, are somewhat fragile and soft. In a preferred embodiment, aminimum of tamping/compaction force is desired to achieve the orallydisintegrating property (low density). Experiments have determined thatlow force compaction without application of RF energy produced veryfragile tablets that could not withstand the forces of material handlingrequired in manufacturing. It was also determined that when a compactedtablet described above is carefully handled and brought to a heat source(RF or conventional convection/conduction) the tablet “slumps” anddeforms under its own weight as the binders become molten.

In most thermodynamic processes or machines, the heat source and theheat sink are two distinct machines or steps requiring material to betransferred from one apparatus to the other. In the manufacture of thetablets of the present invention, the energy must be added to the tabletto achieve the binding effect and then must be removed from the productto solidify and strengthen it for its final handling packaging and use.One of the unique and unanticipated attributes of one embodiment of themanufacturing process of the present invention is that heat source andheat sink are part of the same apparatus. In fact in early experimentsthe metallic forming tool (e.g., a die punch) which was at roomtemperature removed so much heat from the treated tablet shape (due toits high thermal conductivity) that the surface of the resulting tabletwas unacceptable due to the fact that uniform melting within the powderblend had not taken place. The resulting tablet had a well formed core,but the surface was loose unbound and poorly formed powder that did notadhere to the rest of the tablet. To correct for this thermal loss, inone embodiment, heat is added to the forming tools to achieve propersintering at the surface as well as at the center of the tablet.

To exploit this unique thermal effect, powder blends can also be chosenfor their thermal properties and thermal conductivity and specific heatsuch that the powder blend particles themselves become heat sinks. In atypical orally disintegrating tablet (“ODT”) formulation the polarbinders that heat in the RF field may compose less than 10% of themixture. The remaining 90% of the materials act as a heat sink thatquickly removes heat from the binders once the RF field is removed. Thedesirable result of this is that the total process time can be just afew seconds and that the tablet does not need to be transferred from thedie platen during the critical tamping and heating process. The dieplaten can function then as a material handling apparatus as well as athermal forming tool. This is particularly advantageous for successfulmanufacture of fragile orally disintegrating tablets.

In one embodiment, the compaction step (e.g., tamping) which occursprior to the addition of the RF energy utilizes a compaction force whichis less than the force required to compress a chewable or swallowabletablet. In one embodiment, the compaction force is less than about 1000pounds per square inch (e.g., less than about 500 pounds per squareinch, such as less than 200 pounds per square inch, such as less than 50pounds per square inch). In one embodiment, the energy is applied whilethe powder blend is under such force.

In one embodiment, the compaction step occurs in an indexed manner,where one set of tablets are compacted simultaneously, before rotatingto another indexing station. In one embodiment, the compaction stepoccurs at a single indexing station and the application of RF energyoccurs at a separate indexing station. In another embodiment, a thirdindexing station is present wherein the ejection of the tablet ormultiple tablets occurs, wherein the lower forming tool is raised upthrough and up to the surface of the die. In another embodiment thecompaction step is performed through the addition of air pressure orhydraulic cylinder to the top of the upper forming tools. In oneembodiment multiple tablets are ejected simultaneously and separatedfrom the surface of the indexing station and removed via a take-off bar.

In another embodiment, the tablet shape may be prepared by thecompaction methods and apparatus described in United States PatentApplication Publication No. 20040156902. Specifically, the tablet shapemay be made using a rotary compression module including a fill zone,insertion zone, compression zone, ejection zone, and purge zone in asingle apparatus having a double row die construction. The dies of thecompression module may then be filled using the assistance of a vacuum,with filters located in or near each die. The purge zone of thecompression module includes an optional powder blend recovery system torecover excess powder blend from the filters and return the powder blendto the dies. In one embodiment the RF energy source is projected throughthe die table of a rotary press into the appropriate electrode withinthe forming tool or the forming cavity. In one embodiment the die tableis constructed of non-conductive material.

In another embodiment, a portion of the tablet shape may be prepared bya wet-granulation method, in which the excipients and a solution ordispersion of a wet binder (e.g., an aqueous cooked starch paste orsolution of polyvinyl pyrrolidone) are mixed and granulated. Suitableapparatus for wet granulation include low shear mixers (e.g., planetarymixers), high shear mixers, and fluid beds (including rotary fluidbeds). The resulting granulated material may then be dried, andoptionally dry-blended with further ingredients (e.g., excipients suchas, for example, the meltable binder described in the invention herein,lubricants, colorants, and the like). The final dry blend is thensuitable for compaction by the methods described herein. Methods fordirect compaction and wet granulation processes are known in the art.

In one embodiment, the tablet shape is prepared by the compactionmethods and apparatus described in issued U.S. Pat. No. 6,767,200.Specifically, the tablet shape is made using a rotary compression moduleincluding a fill zone, compression zone, and ejection zone in a singleapparatus having a double row die construction as shown in FIG. 6therein. The dies of the compression module are preferably filled usingthe assistance of a vacuum, with filters located in or near each die.

The tablet shape may have one of a variety of different shapes. Forexample, the tablet shape may be shaped as a polyhedron, such as a cube,pyramid, prism, or the like; or may have the geometry of a space figurewith some non-flat faces, such as a cone, truncated cone, triangle,cylinder, sphere, torus, or the like. In certain embodiments, a tabletshape has one or more major faces. For example, the tablet shape surfacetypically has opposing upper and lower faces formed by contact with theupper and lower forming tool faces (e.g., die punches) in the compactionmachine. In such embodiments, the tablet shape surface typically furtherincludes a “belly-band” located between the upper and lower faces, andformed by contact with the die walls in the compaction machine. A tabletshape/tablet may also be a multilayer. Applicants have found that sharpedges in the tooling used to make the tablets can cause arcing, and thusmore rounded edges may be needed.

In one embodiment, the method of producing the tablet shape issubstantially free of the use of solvents. In this embodiment, thepowder blend is substantially free of solvents, and the manufacturingprocess (e.g., filling process into the die) is also substantially freeof solvents. Solvents may include, but are not limited to, water,organic solvents such as but not limited to alcohols, chlorinatedsolvents, hexanes, or acetone; or gaseous solvents such as but notlimited to nitrogen, carbon dioxide or supercritical fluids.

In one embodiment a vibratory step is utilized (e.g., added afterfilling of the powder blend but prior to the heating or fusing step, inorder to remove air from the powder blend). In one embodiment avibration with the frequency from about 1 Hz to about 50 KHz is addedwith amplitude from 1 micron to 5 mm peak-to-peak to allow for theflowable powder blend to settle into the cavity of a the die platen(“forming cavity”).

In one embodiment, as shown in FIGS. 1A-1F, a metered volume of powderblend 4 is filled into a Teflon® (or similar electrical and RF energyinsulative material such as ceramic or UHMW plastic) die platen 2. Dieplaten 2 has forming cavity 5 with inner wall 6, upper opening 7 on theupper surface of die platen 2 (which allows powder blend 4 and upperforming tool 1 to move into the forming cavity 5), and lower opening 8on the opposite surface of die platen 2 (which allows powder blend 4 andlower forming tool 3 to move into the forming cavity 5). Powder blend 4may be either gravity fed or mechanically fed from a feeder (not shown).A metallic, electrically conductive lower forming tool 3 is insertedinto the die platen to retain the powder blend 4, within die platen 2. Asimilar metallic, electrically conductive upper forming tool 1 ispositioned above the die platen 2 as shown in FIG. 1B. The forming tools1 and 3, die platen 2, and powder blend 4 are then moved to a compactionand RF heating station as shown in FIG. 1C to form tablet shape 4 a.

This heating station is comprised of an RF generator 7 which producesthe necessary high voltage, high frequency energy. The generator 7 iselectrically connected to movable upper RF electrode plate 8 and movablelower RF electrode plate 6. As shown in FIG. 1C, at this position, thepowder blend 4 is compacted between an upper forming tool 1 and a lowerforming tool 3 by pressure exerted by upper RF electrode plate 8 andlower electrode plate 6 to form tablet shape 4 a. Tablet shape 4 a isthen exposed to RF energy from RF generator 7, which heats the meltablebinder within tablet shape 4 a. After the RF energy is switched off,tablet shape 4 a cools to form the tablet 4 b. In one embodiment, asshown in FIG. 1D, tablet 4 b is pushed by upper forming tool 1 from thedie platen 2 into blister 8, which is used to package tablet 4 b. In analternative embodiment, as shown in FIG. 1E, tablet 4 b is pushed fromthe die platen 2 by the lower forming tool 3 and guided to an ejectionchute by a stationary “take-off” bar (not shown). FIG. 1F shows a 3dimensional representation of the forming tools 1 and 4, die platen 2,and tablet 4 b.

In FIGS. 2A-2H, an alternate embodiment of the invention is shown wherea multilayer tablet is produced. First, powder blend 10 is filled intodie platen 2 as shown in FIG. 2A. Powder blend 10 is tamped or moveddown into die platen 2 by upper forming tool 1 as shown in FIG. 2B toform tablet shape 10 a. Then, powder blend 11 is then filled on top oftablet shape 10 a. The forming tools 1 and 3, die platen 2, tablet shape10 a and powder blend 11 are then moved to the compaction and RF heatingstation as shown in FIG. 2E. RF heating is accomplished as describedabove in FIG. 1C to produce multilayer tablet 12 as shown in FIGS. 2Fand 2G. While a bi-layer tablet is shown in the drawing, additionalmultiple layers can be produced by adding additional powder blends todie platen 2.

FIGS. 3A-3G show another embodiment of the invention where preformedinserts 30 and 31 are inserted into tablet shape 20 a as shown in FIGS.3A-3D. Forming tools 1 and 3, die platen 2, tablet shape 20, andpreformed inserts 30 and 31 are then moved to the compaction and RFheating station as shown in FIG. 3E. RF heating is accomplished asdescribed above in FIG. 1C to produce a multi-component tablet 40 shownin FIGS. 2F and 2G.

FIGS. 4A and 4B show two views of a rotary indexing machine 195 which isdesigned to create large quantities of tablets. In particular, theconfiguration of the apparatus shown is designed to manufacture fragiletablets with minimized risk of damaging them as they are moved throughthe various manufacturing steps. This embodiment of the invention iscomprised of an indexing table 170 having four sets of die platens 175each having sixteen cavities, powder feeder 100, RF generator 150, amachine frame 140, moving RF electrode assemblies 120 and 130, lowerforming tool assembly 110, upper forming tool assembly 210, tabletejection station 160, indexer drive system 180, blister package web 190,and blister lid material roll 191.

FIG. 5A is a top view of the apparatus in the dwell position. FIG. 5B isa top view of the apparatus as the indexing table 170 rotates betweenstations in direction “A”. FIG. 6A depicts a section view through thelower forming tool assembly 110 in a start position of the manufacturingcycle. The lower forming tools 111, which are made of an electricallyconductive metallic material such as brass or stainless steel, areretained in retainer plate 112 (e.g., made of aluminum or steel). Heatedblock 117 is attached to the retainer plate 112 and contains fluidpassages 117 b. Heated (or optionally cooling) fluid is circulatedthrough the heated block 117 by connections to flexible hoses 119 a and119 b which form a supply and return circuit. Heating can also beaccomplished by electric cartridge heaters or other suitable means (notshown). Attached to the retainer plate are cam-follower 114 and linearbearing 113. A guide shaft 116 is fixed to indexing table 170. Theretainer plate and forming tools 111 and are moveable up or downaccording to the profile of barrel cam 115 which cam follower 114 rollsupon. Also shown is die platen 171, which is made of electrical and RFenergy insulative material such as Teflon, UHMW, or ceramic. This isnecessary to prevent a short circuit when the electrically conductiveforming tools are positioned in the RF electric field in subsequentsteps. The forming cavity 171 a is shown empty at this stage of theprocess.

FIG. 6B depicts a section through the powder feeder station 100 of theapparatus. In this station powdered powder blend 101 is gravity fed intodie platen 171. Movable cam segment 118 is adjusted up or down indirection “B” to vary the volume of the forming cavity 171 a by changingthe amount that the lower forming tools 111 penetrate into the dieplaten 171. This adjustable volume feature enables the precise dose ofpowdered powder blend to be selected for a desired tablet weight. Whenthe machine indexes out of the powder feeder station, the rim of feeder102 scrapes against the die platen 171 to create a level powder surfacerelative to the surface of the die platen 171.

FIG. 7 is a section view through the RF station of the apparatus. The RFgenerator 150 is depicted symbolically here. In one embodiment, theconfiguration of the RF generator 150 is a free running oscillatorsystem. It is typically composed of a power vacuum tube (such as atriode), a DC voltage source between 1000 and 8000 volts connectedacross the cathode and plate (anode). A tank circuit is used to impose asinusoidal signal upon the control grid and electrodes thereby producingthe necessary frequency (typically 13.56 MHZ or 27.12 MHZ) and highvoltage field. An example of such RF generator 150 is the COSMOS ModelC10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, N.Y.). Inanother embodiment, RF energy can be provided by a 50 Ohm systemcomposed of a waveform generator which feeds a radio frequency signal topower amplifiers which are coupled to the electrodes and the load by animpedance matching network.

In FIG. 7, a lower movable RF electrode 121 is shown, movable indirection “D”. It is represented in its down position. The linearmovement is generated by linear actuators which are typically devisessuch as air cylinders or servo motors. Two air cylinders are depicted inFIG. 7. Air cylinder bodies 141 and 142 apply pressure to guide rods 144and 143. Moving platens 132 and 122 are connected to the guide rods andprovide an electrically isolated mounting for electrode plates 131 and121. RF generator 150 connects to the electrode plates 131 and 121through wires 185 and 184. A movable upper RF electrode assembly 130,movable in direction “C”, is shown in its up position. Upper formingtools 133, retainer plate 134, and heated block 135 are all attached tothe movable RF electrode plate 131 and, consequently, move up and downwith it. Powder blend 101 is within die platen 171.

FIG. 8 is a section through the same RF station but shows the RFelectrodes 131 and 121 pressing against the respective forming toolassemblies 133 and 111 to both compact and apply RF energy to powderblend 101 creating tablet 101 a. After application of the RF energy isstopped, the moveable RF electrode plates retract, and the indexingplate 170, die platen 171, and lower forming tool assembly 110 areindexed to the next station.

FIG. 9 is a section view through the tablet ejection station 160.Ejector pins 161 are attached to movable plate 162 (movable in the “E”direction), which is actuated by actuator assembly 163 (for example,this can be a linear servo motor or air cylinder or other suitableactuator). Actuator rod 166 connects to the movable plate 162. Linearbearing 164 and guide rod 165 provide rigidity and support for theactuator plate 162 and prevent destructive side loads created by theejection force from acting upon actuator 163. A blister package 190 isshown below die platen 171.

FIG. 10 is a section through the same assembly after the ejector pins161 have pushed finished tablets 101 a through the die platen 171. Thisdirect placement of tablet into blister helps prevent breakage thatcould occur while using typical means such as feeders or by dumpingtablets into transport drums.

In one embodiment, a lubricant is added to forming cavity prior to theaddition of the flowable powder blend. This lubricant may be a liquid orsolid. Suitable lubricants include but are not limited to solidlubricants such as magnesium stearate, starch, calcium stearate,aluminum stearate and stearic acid; or liquid lubricants such as but notlimited to simethicone, lecithin, vegetable oil, olive oil, or mineraloil. In certain embodiments, the lubricant is added at a percentage byweight of the tablet of less than 5 percent, e.g. less than 2 percent,e.g. less than 0.5 percent. In certain embodiments, the presence of ahydrophobic lubricant can disadvantageously compromise thedisintegration or dissolution properties of a tablet. In one embodimentthe tablet is substantially free of a hydrophobic lubricant. Hydrophobiclubricants include magnesium stearate, calcium stearate and aluminumstearate.

Radiofrequency Heating of Tablet Shape to Form Tablet

Radiofrequency heating generally refers to heating with electromagneticfield at frequencies from about 1 MHz to about 100 MHz. In oneembodiment of the present invention, the RF-energy is within the rangeof frequencies from about 1 MHz to about 100 MHz (e.g., from about 5 MHzto 50 MHz, such as from about 10 MHz to about 30 MHz). The RF-energy isused to heat the binder (e.g., either directly when the meltable binderis a RF-meltable binder or indirectly when the meltable binder is not aRF meltable binder but is heated by a RF-heatable ingredient within thepowder blend). The degree of compaction, the type and amount of meltablebinder, and the amount of RF energy used can determine the hardnessand/or type of tablet whether an oral disintegrating tablet or a softchewable tablet is manufactured.

RF energy generators are well known in the art. Examples of suitable RFgenerators include, but are not limited to, COSMOS Model C10X16G4(Cosmos Electronic Machine Corporation, Farmingdale, N.Y.).

In one embodiment, the upper and lower forming tools serve as theelectrodes (e.g., they are operably associated with the RF energysource) through which the RF energy is delivered to the tablet shape. Inone embodiment, there is direct contact between at least one RFelectrode (e.g., forming tool) and the tablet shape. In anotherembodiment, there is no contact between any of the RF electrode (e.g.,forming tools) and the tablet shape. In one embodiment, the RFelectrodes are in direct contact with the surface of the tablet shapewhen the RF energy is added. In another embodiment, the RF electrodesare not in contact (e.g., from about 1 mm to about 1 cm from the surfaceof the tablet shape) during the addition of the RF energy.

In one embodiment, the RF energy is delivered while the tablet shape isbeing formed. In one embodiment, the RF energy is delivered once thetablet shape is formed. In one embodiment, the RF energy is deliveredafter the tablet shape has been removed from the die.

In one embodiment, the RF energy is applied for a sufficient time tosoften and melt substantially all (e.g., at least 90%, such as at least95%, such as all) of the binder within the tablet shape. In oneembodiment, the RF energy is applied for a sufficient time to soften andmelt only a portion (e.g., less than 75%, such as less than 50%, such asless than 25%) of the binder within the tablet shape, for example onlyon a portion of the tablet shape, such as the outside of the tabletshape.

In alternate embodiments of the invention, the forming tools can beconstructed to achieve localized heating effects and can also beconfigured to shape the electric field that is developed across thetools. FIG. 11A shows one such configuration. An RF generator 200 isconnected to RF electrode plates 201 and 202. Forming tools 205 and 204are constructed of an electrically conductive material and they have anattachment 207 and 208 which are made of electrical and RF energyinsulative material such as ceramic, Teflon®, polyethylene, or highdensity polyethylene. Die platen 203 is also constructed of electricaland RF energy insulative material. This configuration creates greaterdistance between the conductive forming tools to weaken the electricfield which is beneficial for producing thin tablets without the risk ofan electric arc forming which would damage the product and tooling. FIG.11B depicts a similar configuration but with forming tools 210 and 211that, respectively, have a recess containing insert 213 and 212 whichare made of electrical and RF energy insulative material. This geometrywill produce a tablet with lesser heating in the area where the inserts213 and 212 are located since the electric field is weaker due to thegreater distance between the conductive portions of 211 and 210. FIG.11C is similar to FIG. 11B only the geometry is reversed so the tabletformed by this configuration will have a greater heating effect at thecenter since the inserts 216 and 217 are at the periphery of respectiveforming tools 214 and 215. FIG. 11D depicts another embodiment wherebythe die platen is constructed of an electrically conductive component221 and electrically insulating component 222, which is made ofelectrical and RF energy insulative material.

Forming tools 219 and 218 are electrically conductive, but forming tool218 further contains second electrically insulating component 220 aroundthe surface of upper forming tool 218 which contact tablet shape 206.This configuration creates an electric field and associated zones ofheating that is preferential to the conductive portions of the dieplaten.

FIG. 12A is similar to FIG. 11D except the die platen 233 in thisembodiment is constructed entirely of electrically conductive material.FIGS. 12B and 12C depict two embodiments where the die platen comprisesa respective center portion 245 and 254 that are electrically conductiveand respective outer portions 244/246 and 252/253 is are made ofelectrical and RF energy insulative material. FIG. 12B further includesinsulating component 220 around the surface of lower forming tool 219.FIG. 12D is a further embodiment where the forming tools 263 and 262 aremade of electrical and RF energy insulative material. The die platenportions 264 and 265 are made of electrical and RF energy insulativematerial, but there are two respective electrically conductive portions267 and 266 which are attached to the RF generator circuit 200. In thisconfiguration, the electric field is applied in the horizontal directionacross the tablet shape 206.

As described above, the distance between conductive portions of theforming tool has a strong effect on field strength and heating effect.To create a tablet with uniform heating and texture, a forming tool thatis constructed with equidistant spacing is desirable. FIGS. 13A and 13Bdepict such a configuration. In this embodiment, a wave-shaped formingtools 270 and 273 are shown to create a tablet 272 within die platen 271with a unique appearance. The profiles of the forming tool surfaces areequidistant as shown by dimension “X”.

FIG. 14 is an embodiment wherein a non-uniform heating is used tomanufacture tablet 282. In this embodiment, a tablet with hard and softzones is created. The forming tools 280 and 281 are made withprotrusions at the surface that create high field strength (resulting ingreater heating) where they are closest together (shown by the dimension“Z”) and weaker field strength (resulting in lesser heating) where theyare further apart (shown by the dimension “Y”).

In one embodiment, to help reduce sticking, the tablet is cooled withinthe forming cavity to cool and/or solidify the binder. The cooling canbe passive cooling (e.g., at room temperature) or active cooling (e.g.,coolant recirculation cooling). When coolant recirculation cooling isused, the coolant can optionally circulate through channels inside theforming tools (e.g., punches or punch platen) and/or die or die platen(e.g., as discussed above in FIGS. 6A and 6B). In one embodiment, theprocess uses a die platen having multiple die cavities and upper andlower punch platens having multiple upper and lower punched forsimultaneous forming of a plurality of tablets wherein the platens areactively cooled.

In one embodiment, there is a single powder blend forming the tabletshape which is then heated with the RF energy. In another embodiment,the tablet is formed of at least two different powder blends, at leastone powder blend being RF-curable and at least one formulation being notRF-curable. When cured with RF energy, such tablet shape develops two ormore dissimilarly cured zones. In one embodiment, the outside area ofthe tablet shape is cured, while the middle of the tablet shape is notcured. By adjusting the focus of the RF heating and shape of the RFelectrodes, the heat delivered to the tablet shape can be focused tocreate customized softer or harder areas on the finished tablet.

In one embodiment the RF energy is combined with a second source of heatincluding but not limited to infrared, induction, or convection heating.In one embodiment, the addition of the second source of heat isparticularly useful with a secondary non-RF-meltable binder present inthe powder blend.

Microwave Heating of Tablet Shape to Form Tablet

In one embodiment, microwave energy is used in place of radiofrequencyenergy to manufacture the dosage form (e.g., tablet). Microwave heatinggenerally refers to heating with electromagnetic field at frequenciesfrom about 100 MHz to about 300 GHz. In one embodiment of the presentinvention, the RF-energy is within the range of frequencies from about500 MHz to about 100 GHz (e.g., from about 1 GHz to 50 GHz, such as fromabout 1 GHz to about 10 GHz). The microwave energy is used to heat thebinder (e.g., either directly when the meltable binder is susceptible tomicrowave energy (“microwave meltable binder”) or indirectly when themeltable binder is not a microwave meltable binder but is heated by amicrowave heatable ingredient within the powder blend. In such anembodiment, a microwave energy source and microwave electrodes are usedin the machine used to manufacture the dosage form.

Manufacture of Tablet with Varying Surface Hardness and/or Thickness

As discussed above, in one embodiment, the present invention features atablet, wherein the shape of said tablet includes at least one majorface (i.e., the largest side of the tablet) wherein the peak penetrationresistance (described below) at the perimeter (i.e., at the edge) ofsaid major face of the tablet is at least about 10% greater than thepeak penetration resistance at the center of said major face. An exampleof such a tablet is depicted in FIG. 15B, wherein tablet 300 has anupper major face 301, a lower major face 302, and a side 303. In theembodiment of FIG. 15B, upper major face 301 has two regions havedifferent hardness (e.g., a measured by the average peak penetrationresistance); namely perimeter region 304 (i.e., at the perimeter of theupper major face) and center region 305 (i.e., at the center of theupper major face). In one embodiment, as shown in FIG. 15B, centerregion 305 is raised (e.g., thicker) as compared to perimeter region 304

In one embodiment, such tablets having varying surface hardness may bemanufactured but utilizing modified forming tools. For example, in oneembodiment, the machine includes: (a) a die platen having one or moreforming cavities each having an inner wall, a first opening at thesurface of one side of the die platen, and a second opening at thesurface on the opposite side of the die platen; (b) one or more firstforming tools having a dosage form contacting first surface, each of theone or more first forming tools adapted to move into one of the cavitiesthrough the first opening of the forming cavity; (c) one or more secondforming tools having a dosage form contacting second surface, each ofthe one or more second forming tools adapted to move into one of thecavities through the second opening of the forming cavity; (d) at leastone first RF electrode operably associated with the one or more firstforming tools, the one or more second forming tools, or the inner wallof the one or more forming cavities; and (e) at least one second RFelectrode operably associated with the one or more first forming tools,the one or more second forming tools, or the inner wall of the one ormore forming cavities; wherein at least a portion of the dosage formcontacting first surface and/or at least a portion of the dosage formcontacting second surface is movable and wherein the machine is adaptedto form a dosage form between the dosage form contacting first surfaceand the dosage form contacting second surface within a forming cavityand wherein the first RF electrode and the second RF electrode arearranged within the machine such that when RF energy is conductedbetween the first RF electrode and the second RF electrode, the RFenergy passes through the portion of the forming cavity adapted to formthe dosage form.

The present invention features a method of making a solid dosage formusing such a machine, the method including the steps of: (a) adding apowder blend to a forming cavity; (b) moving a first forming tool intothe forming cavity through the first opening of the forming cavity suchthat the powder blend is formed into the shape of the dosage form withinthe forming cavity between the dosage form contacting first surface andthe dosage form contacting second surface; (c) conducting RF energybetween the first electrode and the second electrode such that theenergy heats the powder blend within the forming cavity to form thedosage form; and (d) removing the dosage form from the forming cavity.

Examples of such forming tools are depicted in the embodiment of FIGS.15A and 15B. In this embodiment, upper forming tool 370 has an upperflexible dosage form contacting surface 391 and upper recess 381, andlower forming tool 373 has a lower flexible dosage form contactingsurface 390 and lower recess 380. In this embodiment, RF generator 200are attached to RF electrode plates 201 and 202, and upper forming tool370 and lower forming tool 273 are constructed of electricallyconductive material. Contacting surfaces 390 and 391 are made offlexible RF insulative material, such as Teflon®. Die platen 271 is alsoconstructed of electrical and RF insulative material. As powder blend272 is heated with the RF energy from the RF electrode plates 201 and202, the powder blend 272 expands and causes contacting surfaces 390 and391 to respectively move (e.g., flex) into recesses 381 and 380. As aresult, as depicted in FIG. 15B, the major face 301 of tablet 300 has araised center region 305, which also is less hard than perimeter region304.

In another embodiment that is depicted in FIG. 16, forming tools areconstructed with a movable piston that allows the volume of a portion ofthe forming cavity to expand under RF heating. As illustrated in FIG.16, an upper forming tool assembly 410 and a lower forming tool assembly420 are respectively comprised of an outer forming tool sleeves 401 and406, a movable pistons 402 and 405, and compression springs 403 and 407.Die platen 271 is constructed of electrical and RF insulative material.As powder blend 272 is heated with the RF energy from the RF electrodeplates 201 and 202. As RF energy is applied, powder blend 272 expandsagainst the movable pistons 402 and 405 overcoming the spring preloadforce and pushing the pistons back into the forming tool sleeves 401 and406. Although the springs 403 and 407 depicted in this embodiment enablean automatic expansion feature, a similar effect can be accomplished byother non spring actuated means such as a by actuating the movablepistons by a cam, an air cylinder, or a servomotor or other similarmechanical means.

As discussed above, in one embodiment, the thickness at the perimeter ofthe major face(s) of the tablet is greater than the thickness at thecenter of the tablet. Such tablets with a raised parameter on thesurface of the major face(s) can be made with forming tools depicted inFIGS. 11E and 11F. For example, in one embodiment that is depicted inFIG. 11E, an upper forming tool assembly and a lower forming toolassembly are respectively comprised of an outer forming tool sleeves 501and 506, Teflon® plugs 502 and 505, and metal pins 503 and 507. As RFenergy is applied from RF generator 200 and RF electrode plates 201 and202, metal pins 503 and 507 assist in focusing energy to the center ofthe powder blend 272 within die platen 271. In another embodiment thatis depicted in FIG. 11F, metal pins 503 and 507 are removed, resultingin less RF energy being transferred to the tablet.

In one embodiment, the thickness of the tablet at the center region ofthe major face is different than the thickness at the perimeter of themajor face (e.g., thicker or thinner). In one embodiment, there are twomajor faces of the tablet wherein only one center region is expanded orcontracted with respect to the perimeter of the same face. In oneembodiment, wherein the center region is expanded, the ratio of thethickness at the center to the thickness of at the perimeter is at leastabout 1.1:1 for example at least about 1.3:1. In one embodiment, whereinthe perimeter is thicker, the ratio of the thickness at the perimeter tothe center is at least about 1.1:1, for example at least about 1.3:1.

In one embodiment, the radius of curvature at the center of the tabletface is substantially different than the radius of curvature of thetablet face at the perimeter region. For example the radius of curvatureat the center of the tablet face may be at least 10% or at least 50%less than the radius of curvature of the tablet face in the perimeterregion.

Inserts within Tablet Shape

In one embodiment, an insert is incorporated into the tablet shapebefore the RF energy is delivered. Examples include solid compressedforms or beads filled with a to liquid composition. Such incorporationof an insert is depicted in FIGS. 3A-3G.

In one embodiment the pharmaceutically active agent is in the form of agel bead, which is liquid filled or semi-solid filled. The gel bead(s)are added as a portion of the powder blend. In one embodiment, thetablet of this invention has the added advantage of not using a strongcompaction step, allowing for the use of liquid or semisolid filledparticles or beads which are deformable since they will not rupturefollowing the reduced pressure compaction step. These bead walls maycontain gelling substances such as: gelatin; gellan gum; xanthan gum;agar; locust bean gum; carrageenan; polymers or polysaccharides such asbut not limited to sodium alginate, calcium alginate, hypromellose,hydroxypropyl cellulose and pullulan; polyethylene oxide; and starches.The bead walls may further contain a plasticizer such as glycerin,polyethylene glycol, propylene glycol, triacetin, triethyl citrate andtributyl citrate. The pharmaceutically active agent may be dissolved,suspended or dispersed in a filler material such as but not limited tohigh fructose corn syrup, sugars, glycerin, polyethylene glycol,propylene glycol, or oils such as but not limited to vegetable oil,olive oil, or mineral oil.

In one embodiment, the insert is substantially free of RF-absorbingingredients, in which case application of the RF energy results in nosignificant heating of the insert itself. In other embodiments, theinsert contains ingredients and are heated upon exposure to RF energyand, thus, such inserts can be used to soften or melt the meltablebinder.

Multi-Layer Tablet

In certain embodiments, the tablet includes at least two layers, e.g.,with different types and/or concentrations of binders and/or otheringredients or different concentrations of pharmaceutically activeagents. Such an embodiment is shown in FIGS. 2A-2D. In one embodiment,the tablet includes two layers, one layer having orally disintegratingproperties and another layer being chewable or swallowable. In oneembodiment, one layer has a meltable binder and another layer does nothave a meltable binder. In one embodiment one layer is compacted athigher compaction force versus the other layer. In one embodiment, bothlayers contain same amount of the meltable binder, but have differentamount of pharmaceutically active agents and/or other excipients. In oneembodiment, all properties of the two layers are identical but thecolors of the two layers are different.

Effervescent Couple

In one embodiment, the powder blend further contains one or moreeffervescent couples. In one embodiment, effervescent couple containsone member from the group consisting of sodium bicarbonate, potassiumbicarbonate, calcium carbonate, magnesium carbonate, and sodiumcarbonate, and one member selected from the group consisting of citricacid, malic acid, fumaric acid, tartaric acid, phosphoric acid, andalginic acid.

In one embodiment, the combined amount of the effervescent couple(s) inthe powder blend/tablet is from about 2 to about 20 percent by weight,such as from about 2 to about 10 percent by weight of the total weightof the powder blend/tablet.

Orally Disintegrating Tablet

In one embodiment, the tablet is designed to disintegrate in the mouthwhen placed on the tongue in less than about 60 seconds, e.g. less thanabout 45 seconds, e.g. less than about 30 seconds, e.g. less than about15 seconds.

In one embodiment, the tablet meets the criteria for OrallyDisintegrating Tablets (ODTs) as defined by the draft Food and DrugAdministration guidance, as published in April, 2007. In one embodiment,the tablet meets a two-fold definition for orally disintegrating tabletsincluding the following criteria: 1) that the solid tablet is one whichcontains medicinal substances and which disintegrates rapidly, usuallywithin a matter of seconds, when placed upon the tongue and 2) beconsidered a solid oral preparation that disintegrates rapidly in theoral cavity, with an in vitro disintegration time of approximately 30seconds or less, when based on the United States Pharmacopeia (USP)disintegration test method for the specific medicinal substance orsubstances.

Additional Edible Portion

In one embodiment, the tablet is contained next to another edible form.In one embodiment, this edible form is a hard candy or compressed ringthat holds the powder blend during compaction and/or the RF heatingstep.

In one embodiment, the outer hard candy form may be made using uniplastrolling or roping and subsequent cutting and stamping, as well asdepositing into molds. The hard candy portion contains one or moresugars selected from the group consisting of isomalt, sucrose, dextrose,corn syrup, lactitol, and lycasin. In one embodiment, the hard candyportion contains at least 50% (such as at least 75%, such as at least90%) by weight of such sugar(s).

In one embodiment, the outer edible form contains a pharmaceuticallyactive agent and the inner tablet contains a second portion of the samepharmaceutically active agent that is in the outer edible form. In oneembodiment, the outer edible form contains a pharmaceutically activeagent and the inner tablet contains a different pharmaceutically activeagent than that in the outer edible form. In one embodiment, the outeredible form disintegrates at a rate of at least 10 times, such as atleast 20 times, the rate of the inner tablet. The first and secondportions can be the same or different.

In one embodiment, the tablet having an outer edible form and an innertablet is coated with an immediate release sugar coating or filmcoating. In one embodiment, to produce such a tablet, the step followingthe fusing (heating) and subsequent cooling of the tablet would involvefurther sugar or film coating in a coating pan.

Hardness/Density of Tablet

In one embodiment, the tablet is prepared such that the tablet isrelatively soft (e.g., capable of disintegrating in the mouth or beingchewed). In one embodiment, the hardness of the tablet is preferablyless than about 3 kiloponds per square centimeter (kp/cm²) (e.g., lessthan about 2 kp/cm², such as less than about 1 kp/cm²).

Hardness is a term used in the art to describe the diametral breakingstrength as measured by conventional pharmaceutical hardness testingequipment, such as a Schleuniger Hardness Tester. In order to comparevalues across different size tablets, the breaking strength must benormalized for the area of the break. This normalized value, expressedin kp/cm², is sometimes referred in the art as tablet tensile strength.A general discussion of tablet hardness testing is found in Leiberman etal., Pharmaceutical Dosage Forms—Tablets, Volume 2, 2.sup.nd ed., MarcelDekker Inc., 1990, pp. 213-217, 327-329.

A more preferred test for hardness of the tablet of the presentinvention relies upon a Texture Analyzer TA-XT2i to measure the peakpenetration resistance of the tablet. The texture analyzer is fittedwith a flat faced cylindrical probe having a length longer than thethickness of the tablet (e.g., 26 mm) and a diameter of from 1 mm to 2mm. To perform the test, the tablet rests upon a platform fitted with acylindrical die having a cavity. The diameter of the cavity is equal orgreater than the diameter of the probe and less than the diameter of thetablet face (e.g., the die cavity may have a diameter of about 6 mm anda depth of about 25 mm) The texture analyzer is employed to measure andreport the force in grams as the probe moves at 0.05 millimeters persecond through the tablet, until the probe passes through at least 80%of the thickness of the tablet. The maximum force required to penetratethe tablet is referred to herein as the peak resistance to penetration(“peak penetration resistance”).

In one embodiment, the peak penetration resistance at the center of amajor face is less than 2500 grams, such as less than about 1500 grams,such as less than about 500 grams. In one embodiment, the peakpenetration resistance at the center of a major face is from about 2grams to about 2000 grams, such as from about 30 grams to about 1000grams, such as from about 100 grams to about 500 grams.

In one embodiment, the peak penetration resistance at the perimeter of amajor face is less than 3000 grams, such as less than about 2000 grams,such as less than about 1000 grams. In one embodiment, the peakpenetration resistance at the perimeter of the major face of the tabletis from about 50 to about 3000 grams, such as from about 100 to about1500 grams, such as from about 150 to about 1000 grams. In oneembodiment, the peak penetration resistance at the perimeter of themajor face is the average of four equally spaced measurements along theperimeter of the major face.

In one embodiment, the peak penetration resistance of the tablet variesbetween different regions in the tablet. In one such embodiment, thepeak penetration resistance measured at the perimeter is higher than thepeak penetration resistance at the center of a major face. For example,the peak penetration resistance of the tablet at the perimeter may be atleast about 10% greater than the peak penetration resistance at thecenter of a major face, such as at least about 30%, such as at leastabout 100%, such as at least about 200% greater. For example, in oneembodiment, the ratio of the peak penetration resistance of the tabletat the perimeter to the peak penetration resistance at the center of amajor face is at least about 1.1:1, such as at least about 1.3:1, suchas at least about 2:1, such as at least about 3:1. In one particularembodiment, the peak penetration resistance at the center of a majorface is from about 10 grams to about 500 grams and the peak penetrationresistance at the perimeter of the tablet is from about 50 grams toabout 1000 grams, such as the peak penetration resistance at the centerof a major face is from about 50 grams to about 350 grams and the peakpenetration resistance at the perimeter of the tablet is from about 100grams to about 750 grams

In one embodiment, the density of the tablet is less than about 2 g/cc(e.g., less than about 0.9 g/cc, such as less than about 0.8 g/cc, suchas less than about 0.7 g/cc). In one embodiment, the difference in thedensity of the powdered material following the compaction step is lessthan about 40 percent (e.g., less than about 25 percent, such as lessthan about 15 percent).

In one embodiment, the density of the tablet is different between thecenter of the major face of the tablet and the perimeter of the majorface. In one embodiment, the density of 25 percent of the surface areaof the major face of the tablet when measured from the outer perimeteris at least 10 percent greater than the density of 25 percent of thesurface area of the tablet when measured from the center portion. In oneembodiment the density of 25 percent of the surface area of the tabletwhen measured from the outer perimeter is from about 0.6 g/cc to about1.2 g/cc and the density of 25 percent of the surface area of the centerof the tablet is from about 0.1 g/cc to about 0.59 g/cc.

Tablets Coatings

In one embodiment, the tablet includes an additional outer coating(e.g., a translucent coating such as a clear coating) to help limit thefriability of the tablet. Suitable materials for translucent coatingsinclude, but are not limited to, hypromellose, hydroxypropylcellulose,starch, polyvinyl alcohol, polyethylene glycol, polyvinylalcohol andpolyethylene glycol mixtures and copolymers, and mixtures thereof.Tablets of the present invention may include a coating from about 0.05to about 10 percent, or about 0.1 to about 3 percent by weight of thetotal tablet.

Surface Treating of the Dosage Form

In one embodiment, the surface of the dosage form shape and/or thedosage form (e.g., tablet shape and/or tablet) is further treated withenergy (e.g., convection, infrared, or RF energy) to soften or melt thematerial on the surface of the dosage form and then cooled or allowed tocool to further smooth the texture, enhance the gloss of surface of thedosage form, limit the friability of the dosage form, and/or provide amark for identification. In one embodiment, the surface of the dosageform is further exposed to infrared energy wherein the majority (atleast 50 percent, such as least 90 percent, such as at least 99 percent)of the wavelength of such infrared energy is from about 0.5 to about 5micrometers such as from about 0.8 to about 3.5 micrometers (e.g., byuse of a wavelength filter). In one embodiment, the infrared energysource is a quartz lamp with a parabolic reflector (e.g., to intensifythe energy) and a filter to remove unwanted frequencies. Examples ofsuch infrared energy sources include the SPOT IR 4150 (commerciallyavailable from Research, Inc., Eden Prairie, Minn.).

Use of Tablet

The tablets may be used as swallowable, chewable, or orallydisintegrating tablets to administer the pharmaceutically active agent.

In one embodiment, the present invention features a method of treatingan ailment, the method including orally administering theabove-described tablet wherein the tablet includes an amount of thepharmaceutically active agent effective to treat the ailment. Examplesof such ailments include, but are not limited to, pain (such asheadaches, migraines, sore throat, cramps, back aches and muscle aches),fever, inflammation, upper respiratory disorders (such as cough andcongestion), infections (such as bacterial and viral infections),depression, diabetes, obesity, cardiovascular disorders (such as highcholesterol, triglycerides, and blood pressure), gastrointestinaldisorders (such as nausea, diarrhea, irritable bowel syndrome and gas),sleep disorders, osteoporosis, and nicotine dependence.

In one embodiment, the method is for the treatment of an upperrespiratory disorder, wherein the pharmaceutically active agent isselected from the group of phenylephrine, cetirizine, loratadine,fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine,chlophedianol, and pseudoephedrine.

In this embodiment, the “unit dose” is typically accompanied by dosingdirections, which instruct the patient to take an amount of thepharmaceutically active agent that may be a multiple of the unit dosedepending on, e.g., the age or weight of the patient. Typically the unitdose volume will contain an amount of pharmaceutically active agent thatis therapeutically effective for the smallest patient. For example,suitable unit dose volumes may include one tablet.

EXAMPLES

Specific embodiments of the present invention are illustrated by way ofthe following examples. This invention is not confined to the specificlimitations set forth in these examples.

Example 1 Manufacture of Powder Blend Containing Loratadine

The loratadine powder blend for an orally disintegrating tablet,containing the ingredients of Table 1, is manufactured as follows:

TABLE 1 Loratadine Powder Blend Formulation Ingredient G/Batch Mg/TabletDextrose Monohydrate 45.18 120.0 Loratadine 3.765 10.0 PolyethyleneGlycol 4000¹ 24.475 65.0 Maltodextrin² 15.062 40.0 Red Colorant 0.0280.075 Simethicone DC100³ 5.648 15.0 Sucralose USP 1.13 3.0 PolyethyleneOxide 1.883 5.0 Mint Flavor 2.824 7.5 Total 100 265.575 ¹Commerciallyavailable from Clariant PF in Rothausstr, Switzerland ²Commerciallyavailable from National Starch in Bridgewater, NJ ³Commerciallyavailable from SPI Pharma in Wilmington, DE

First, the sucralose, colorant, and flavor were placed together into a500 cc sealable plastic bottle. The mixture was then blendedend-over-end manually for approximately 2 minutes. The resultingmixture, the dextrose monohydrate, loratadine, and the polyethyleneoxide were then added to another 500 cc sealable plastic bottle andmixed end-over-end manually for approximately 5 minutes. The resultingmixture was then added to a planetary bowl mixer, and the simethiconeDC100 was added and mixed for approximately 3 minutes. Lastly, thepolyethylene glycol 4000 and the maltodextrin were added to the mixtureand mixed for approximately 3 minutes.

Example 2 Manufacture of Orally Disintegrating Tablet ContainingLoratadine

A portion of the powder blend from Example 1 was placed into a ½ inchdiameter forming cavity of an electrically insulative Teflon die platen.The powder blend was then tamped between an upper and lower flat-facedmetal forming tools into a shape conformal to the surface of the formingtools. The tamping pressure was typically between 10 and approximately50 psi of pressure. The forming tools, die platen and tablet shape werethen placed between the upper RF electrode and lower RF electrodepowered by an RF heating unit using a COSMOS Model C10X16G4 (CosmosElectronic Machine Corporation, Farmingdale, N.Y.) RF generator havingan output of 4 KW of power, frequency of 27 MHz, and the vacuumcapacitor is set at 140. The forming tools are heated with recirculatingwater at a temperature of 57° C. The upper RF electrode was brought intocontact with the upper forming tool and the lower RF electrode isbrought into contact with lower forming tool. The RF heating unit wasenergized for 2 to 5 seconds. The resulting tablet was then ejected fromthe die platen using the lower forming tool.

Example 3 Manufacture of Orally Disintegrating Tablet ContainingDiphenhydramine

The diphenhydramine powder blend for an orally disintegrating tablet,containing the ingredients of Table 2, was manufactured as follows. Thesucralose, yellow colorant, flavors, polyethylene glycol andmaltodextrin from the formula in Table 2 were passed through a 20 meshscreen. The sieved materials were placed into a 500 cc plastic bottleand blended end over end with the remaining materials in Table 2. Thepowder blend was placed into the forming cavity, tamped, and activatedwith RF energy as described in Example 2 for approximately 2 to 5seconds to form the orally disintegrating tablet and subsequentlyremoved from the die platen.

TABLE 2 Powder Blend Formulation Containing Diphenhydramine (DPH)Ingredient G/Batch Mg/Tablet Dextrose Monohydrate 304.11 219.0Diphenhydramine (Coated)³ 49.57 35.70 Polyethylene Glycol 8000¹ 44.1631.80 Maltodextrin² 88.46 63.70 Yellow Colorant 0.78 0.56 Orange Flavor1.65 1.19 Vanilla Flavor 2.21 1.59 Sucralose USP 1.11 0.80 Citric AcidUSP Anhydrous 7.96 5.73 Total 500.00 360.07 ¹Commercially available fromClariant PF in Rothausstr, Switzerland ²Commercially available fromNational Starch in Bridgewater, NJ ³Encapsulated Diphenhydramine coatedutilizing cellulose acetate and polymethacrylate, utilizing processoutlined in U.S. Pat. No. 5,997,905 incorporated herein by reference

Example 4 Manufacture of Orally Disintegrating Tablet Placebo ContainingDextrose Monohydrate

The placebo powder blend for an orally disintegrating tablet, containingthe ingredients of Table 3, was manufactured as follows. The sucralose,yellow colorant, flavors, polyethylene glycol and maltodextrin from theformula in Table 3 were passed through a 20 mesh screen. The sievedmaterials were placed into a 500 cc plastic bottle and blended end overend with the remaining materials in Table 3. The powder blend was placedinto the forming cavity, tamped, and activated with RF energy asdescribed in Example 2 for approximately 2 to 5 seconds to form theorally disintegrating tablet and subsequently removed from the dieplaten.

TABLE 3 Powder Blend Formulation Ingredient G/Batch Mg/Tablet DextroseMonohydrate 283.04 255.0 Polyethylene Glycol 8000¹ 35.30 31.80Maltodextrin² 70.71 63.70 Yellow Colorant 0.62 0.56 Orange Flavor 1.321.19 Vanilla Flavor 1.76 1.59 Sucralose USP 0.89 0.80 Citric AcidAnhydrous USP 6.36 5.73 Total 400.00 360.37 ¹Commercially available fromClariant PF in Rothausstr, Switzerland ²Commercially available fromNational Starch in Bridgewater, NJ

Example 5 Manufacture of Orally Disintegrating Tablet Placebo ContainingErythritol

The placebo powder blend for an orally disintegrating tablet, containingthe ingredients of Table 4, was manufactured as follows. The sucralose,yellow colorant, flavors, polyethylene glycol and maltodextrin from theformula in Table 4 were passed through a 20 mesh screen. The sievedmaterials were placed into a 500 cc plastic bottle and blended end overend with the remaining materials in Table 4. The powder blend was placedinto the forming cavity, tamped, and activated with RF energy asdescribed in Example 2 for approximately 2 to 5 seconds to form theorally disintegrating tablet and subsequently removed from the dieplaten.

TABLE 4 Placebo Powder Blend Formulation Containing ErythritolIngredient G/Batch Mg/Tablet Erythritol Directly Compressible³ 212.28255.0 Polyethylene Glycol 8000¹ 26.47 31.80 Maltodextrin² 53.03 63.70Yellow Colorant 0.47 0.56 Orange Flavor 0.99 1.19 Vanilla Flavor 1.321.59 Sucralose USP 0.67 0.80 Citric Acid Anhydrous USP 4.77 5.73 Total300.00 360.37 ¹Commercially available from Clariant PF in Rothausstr,Switzerland ²Commercially available from National Starch in Bridgewater,NJ ³Commercially available from Corn Products in Westchester, IL

Example 6 Manufacture of a Comparative Compressed Chewable PlaceboTablet

The placebo powder blend for a comparative chewable placebo tablet,containing the ingredients of Table 5, was manufactured as follows. Thesucralose, yellow color, and flavors were passed through a 20 meshscreen prior to blending. The sieved materials were blended with theremaining materials in the formula in Table 5 and added to a 500 ccplastic bottle and blended end over end for approximately 3 minutes anddischarged. The tablets were compressed using two different compressionforces as follows: Tablets (a) were compressed on a single stationmanual Carver press (commercially available from Carver PressCorporation in Wabash, Ind.) at 0.7 Metric tons (6.86 KiloNewtons) andTablets (b) were compressed at 0.25 Metric tons (2.45 KiloNewtons).Tablets (b) were extremely friable and fragile given the low amount ofpressure applied to the formulation.

TABLE 5 Placebo Powder Blend Formulation for Compressed TabletIngredient G/Batch Mg/Tablet Dextrose Monohydrate 114.773 138.00Polyethylene Glycol 4000¹ 41.584 50.00 Maltodextrin² 35.763 43.00 BlueColorant 0.075 0.0907 Yellow Colorant 0.153 0.1842 Vanilla Flavor 1.8302.20 Sucralose USP 1.248 1.50 Mint Flavor 4.574 5.50 Total 200 240.47¹Commercially available from Clariant PF in Rothausstr, Switzerland²Commercially available from National Starch in Bridgewater, NJ

Example 7 Manufacture of a Comparative Compressed Chewable ContainingAcetaminophen

The placebo powder blend for a chewable tablet, containing theingredients of Table 6, was manufactured as follows. The sucralose,yellow color, flavors, and citric acid were passed through a 20 meshscreen prior to blending. The sieved materials were blended with theremaining materials in the formula in Table 6 and added to a 500 ccplastic bottle and blended end over end for approximately 3 minutes anddischarged. The tablets were compressed using two different compressionforces as follows: Tablets (a) were lightly compressed on a singlestation manual Carver press at 0.7 Metric tons (6.86 KiloNewtons) andTablets (b) were compressed at 0.25 Metric tons (2.45 KiloNewtons).Tablets (b) were extremely friable and fragile given the low amount ofpressure applied to the formulation.

TABLE 6 Powder Blend Formulation Containing Acetaminophen IngredientG/Batch Mg/Tablet Dextrose Monohydrate 32.284 94.00 Acetaminophen(Coated)³ 29.989 87.32 Polyethylene Glycol 4000¹ 5.152 15.00Maltodextrin² 20.607 60.00 Yellow Colorant 0.120 0.35 Orange Flavor0.343 1.00 Vanilla Flavor 0.515 1.50 Sucralose USP 0.343 1.00Crosslinked Povidone⁵ 2.061 6.00 Polyethylene Oxide (Grade WSR 303)⁴6.869 20.00 Citric Acid USP Anhydrous 1.717 5.00 Total 100 291.17¹Commercially available from Clariant PF in Rothausstr, Switzerland²Commercially available from National Starch in Bridgewater, NJ³Encapsulated Acetaminophen coated utilizing cellulose acetate andpovidone, utilizing process outlined in U.S. Pat. No. 4,851,226incorporated herein by reference ⁴Commercially available from the DOWCorporation in Midland, MI ⁵Commercially available as Kollidon CL-M fromthe BASF Corporation in Florham Park, NJ

Example 8 Density Measurements of ODT and Compressed Tablets

Three tablets from each of Examples 3, 4, 5, 6, and 7 were measured todetermine the density of compressed tablets and tablets producedutilizing the method of the present invention. The density wascalculated utilizing the volume of a cylinder as calculated using thewidth and thickness of the tablet divided by the weight of individualtablets.

TABLE 8 Tablet Density Measurements Weight Diameter Height VolumeDensity Example (mg) (mm) (mm) (mm³) (mg/mm³) Example 3 (1) 379 13.135.00 677.0 0.560 Example 3 (2) 403 13.10 4.97 669.9 0.602 Example 3 (3)409 13.03 4.87 649.4 0.630 Example 4 (1) 347 12.90 4.85 633.9 0.547Example 4 (2) 416 12.97 4.96 655.3 0.635 Example 4 (3) 398 13.06 4.95663.1 0.600 Example 5 (1) 419 12.90 5.38 703.2 0.596 Example 5 (2) 39713.15 5.32 722.5 0.549 Example 5 (3) 352 12.87 5.00 650.5 0.541 Example6a (1) 399 11.18 3.32 325.9 1.220 Example 6a (2) 372 11.16 3.06 299.31.240 Example 6a (3) 391 11.18 3.25 319.0 1.230 Example 6b (1) 433 11.204.27 420.7 1.030 Example 6b (2) 442 11.22 4.35 430.1 1.030 Example 6b(3) 404 11.18 3.93 385.8 1.050 Example 7a (1) 364 11.20 3.26 321.2 1.130Example 7a (2) 328 11.18 2.94 288.6 1.140 Example 7a (3) 404 11.17 3.65357.7 1.130 Example 7b (1) 413 11.25 4.66 463.2 0.890 Example 7b (2) 45111.21 5.00 493.5 0.910 Example 7b (3) 437 11.22 4.82 476.6 0.920

As is shown in table 8, the ODT tablets of the present invention(Examples 3, 4, and 5) have densities ranging from 0.541-0.635 mg/mm³,while the comparative chewable tablets of Examples 6 and 7 had densitiesranging from 0.890-1.240 mg/mm³. The ODT tablets of the presentinvention, thus, had densities approximately half of that of thecomparative examples.

Example 9 Disintegration Test Utilizing Texture Analyzer TA XT Plus

The following test was performed utilizing the Texture Analyzer TA XTPlus, commercially available from Texture Technologies in Scarsdale,N.Y. The texture Analyzer was equipped with a TA-55 probe, and set to aprobe speed of 0.1 mm/sec. The individual tablet was placed into a 5 mmgraduated cylinder, and placed onto the short axis. 20 grams of forcewas applied to the tablet via the 5 mm probe. The force was applied andat approx. 10 mL of de-ionized water at 25° C. was added to cover thetablet. The force was analyzed over time and the following tablets wereanalyzed: the tablets of Example 6a and the tablets of Example 3. Thetablets of the present invention (Example 3) disintegrated immediatelyfollowing the addition of the water as indicated by the probe distance,which increased from 0 mm to greater than 1 mm between 10 and 20seconds. The tablets from Example 6a, which were representative ofchewable tablets, disintegrated in 84.30 seconds from the addition ofwater as measured by the change in slope in the texture analyzer, wheretablets of Example 3 were completely disintegrated in 6.99 seconds fromthe addition of water.

Example 10 Manufacture of Powder Blend Containing Loratadine

The loratadine powder blend for an orally disintegrating tablet,containing the ingredients of Table 9, is manufactured as follows:

TABLE 9 Loratadine Powder Blend Formulation Ingredient G/Batch Mg/TabletDextrose Monohydrate 48.86 120 Loratadine 4.07 10 Polyethylene Glycol4000 26.47 65 Maltodextrin 16.29 40 Red Colorant 0.03 0.075 SucraloseUSP 1.22 3 Mint Flavor 3.05 7.5 Total 100 245.575

First, the sucralose, colorant, and flavor are placed together into a500 cc sealable plastic bottle. The mixture is then blended end-over-endmanually for approximately 2 minutes. The resulting mixture, thedextrose monohydrate, and the loratadine, are then added to another 500cc sealable plastic bottle and mixed end-over-end manually forapproximately 5 minutes. Lastly, the polyethylene glycol 4000 and themaltodextrin is added to the mixture and mixed for approximately 3minutes.

Example 11 Manufacture of Orally Disintegrating Tablet

A portion of the powder blend from Example 10 is placed into anelectrically insulative Teflon®, or ceramic die block, approximately0.50″ in diameter and 0.175″ thick. The powder blend is then tampedbetween an upper and lower forming tools into a shape conforming to thesurface of the forming tools. The forming tools are metal and have arecessed center, which covers approximately 80% of the surface area.Covering the entire upper surface of the tool is a thin, flat, flexibleTeflon disc (approximately 0.020-0.100″ thick) as depicted in FIG. 15A.The tamping pressure is typically between 10 and approximately 100 psiof pressure. The forming tools, die block and powder blend are thenplaced between the upper electrode and lower electrode of an RF heatingunit The upper electrode is brought into contact with the upper formingtool and the lower electrode is brought into contact with lower formingtool. The RF heating unit is energized for 2 seconds as described inExample 2. After cooling, the resulting tablet is then ejected from thedie block using the lower forming tool. The resulting tablets have acenter portion which is raised as compared to the perimeter of the twomajor faces.

Example 12 Orally Disintegrating Tablet Placebo Produced Utilizing RfEnergy Comprising Dextrose Monohydrate and Forming Tools with HollowedCenters

The polyethylene glycol are passed through a 30 mesh screen. Thesucralose, yellow colorant, flavors, polyethylene glycol, dextrosemonohydrate and maltodextrin from the formula in Table 10 are passedthrough a 20 mesh screen. The sieved materials are placed into a plasticbag and blended end over end with the remaining materials in Table 10.

The powder blend is placed into an upper and lower set of ½ inch flatfaced forming tools with hollowed centers, and conductive rings.Covering the entire upper surface of the tool is a thin, flat, flexibleTeflon disc (approximately 0.020-0.100″ thick) as depicted in FIG. 15.The powder blend is activated with Rf energy for approximately 2 secondsas described in Example 2 to form an orally disintegrating tablet andsubsequently removed from the die. The tablets that are produced hadraised centers.

TABLE 10 Placebo Powder Blend Formulation Comprising DextroseMonohydrate Ingredient G/Batch Mg/Tablet Dextrose Monohydrate 2319.33138.00 Polyethylene Glycol 4000² 50.00 840.34 Maltodextrin³ 722.69 43.00Peppermint Flavor¹ 92.44 5.50 Sucralose USP 25.21 1.50 Total 4000.0238.00 ¹Commercially available from Virginia Dare in Brooklyn, NY²Commercially available from Clariant PF in Rothausstr, Switzerland³Commercially available from National Starch in Bridgewater, NJ

Example 13 Orally Disintegrating Tablet Placebo Produced Utilizing RfEnergy Comprising Dextrose Monohydrate

The powder blend from Example 12 are placed into an upper and lower setof ½ inch flat faced forming tools as depicted in FIG. 11E or 11F withTeflon® plugs in the center of the forming tool (with or without anadditional metal pin) and activated with Rf energy for approximately 2seconds as described in Example 2 to form an orally disintegratingtablet and subsequently removed from the die. This method producedtablets with a perimeter that was slightly raised as compared to thecenter at the two major faces.

Example 14 Peak Resistance to Penetration at the Major Faces of Tablets

The following test was performed utilizing the Texture Analyzer TA XTPlus, commercially available from Texture Technologies in Scarsdale,N.Y. The average peak resistance to penetration was measured at thecenter (“PRP at Center”) and at the perimeter (“PRP at Perimeter”) ofthe major face using the Texture Analyzer TA-XT2i which was fitted witha 1 or 2 millimeter diameter flat faced probe as described above, andthe ratio was calculated (“Ratio of PRP”). All samples were tested witha 2 mm probe unless otherwise specified in Table 12. The data for thetablets produced according to either Examples 12 or 13 are shown inTable 11. Samples 1-10 of Example 13 were made with forming tools asdepicted in FIG. 11E while Samples 11-18 of Example 13 were made withforming tools as depicted in FIG. 11F. The actual frequency of the RFused to make the tablets is indicated in Table 11 (the frequency wasmeasured using the Agilent Spectrum Analyzer Model N9342C, AgilentTechnologies, Inc., Santa Clara, Calif., USA).

Comparative data from marketed fast dissolving tablet products is shownin Table 12. The following comparative products were tested: Migranin400 mg Ibuprofen Dragees (Reckitt Benckisser Healthcare, GmbH, Manheim,Germany); Nurofen Meltlets Ibuprofen 200 mg Self Dissolving Tablets(Crookes Healthcare, Nottingham, UK); Claritin Reditabs, 10 mgLoratadine (Schering-Plough, Memphis, Tenn.); Imodium Instant MeltTablets, 2 mg Loperamide HCl (McNeil Products LTD, Maidenhead,Berkshire, UK); Alavert Loratadine Orally Disintegrating Tablet, 10 mg(Wyeth Consumer Healthcare, Madison, N.J.); and Calpol SixPlus FastmeltsParacetamol 250 mg Colour and Sugar Free Strawberry Flavor (PfizerConsumer Healthcare, Walton-on-the-Hill, Surrey, KT20 7NS).

TABLE 11 Tablet Peak Resistance to Penetration Testing Measured PRP atPRP at Frequency Perimeter Center Ratio Samples (Mhz) (g) (g) of PRPExample 12 (1) 27.605000 349.6 150.9 2.3:1 Example 12 (2) 27.605000427.5 107.4 4.0:1 Example 12 (3) 27.605000 282.6 136.9 2.1:1 Example 12(4) 27.603109 262.0 100.7 2.6:1 Example 12 (5) 27.603109 196.5 99.42.0:1 Example 12 (6) 27.603109 287.5 110.6 2.6:1 Example 12 (7)27.597750 394.8 121.5 3.2:1 Example 12 (8) 27.597750 429.7 125.4 3.4:1Example 12 (9) 27.597750 434.3 153.6 2.8:1 Example 12 (10) 27.574739546.8 110.8 4.9:1 Example 12 (11) 27.574739 398.5 119.6 3.3:1 Example 12(12) 27.574739 368.4 23.7 15.5:1  Example 13 (1) 27.6326 103.8 0.0 >1:n/a Example 13 (2) 27.6304 237.0 15.5 15.3:1  Example 13 (3) 27.6282322.6 22.5 14.3:1  Example 13 (4) 27.6260 353.8 22.0 16.1:1  Example 13(5) 27.6217 475.5 25.5 18.6:1  Example 13 (6) 27.5978 193.5 18.6 10.4:1 Example 13 (7) 27.5304 659.7 269.9 2.4:1 Example 13 (8) 27.5782 556.5131.0 4.2:1 Example 13 (9) 27.5304 578.5 327.7 1.8:1 Example 13 (10)27.5978 257.4 23.8 10.8:1  Example 13 (11) 27.5820 273.0 69.6 3.9:1Example 13 (12) 27.5950 95.0 35.4 2.7:1 Example 13 (13) 27.560 355.2282.6 1.3:1 Example 13 (14) 27.552 157.4 108.9 1.4:1 Example 13 (15)27.591 107.4 22.0 4.9:1 Example 13 (16) 27.582 61.3 13.0 4.7:1 Example13 (17) 27.582 192.0 56.7 3.4:1 Example 13 (18) 27.595 69.4 0.0  >1:n/aMinimum¹ 61.3 13.0 1.3:1 Maximum 659.7 327.7 18.6:1  ¹“0.0” resultsexcluded from Minimum and numerical ratio calculations

TABLE 12 Tablet Penetration for Comparative Products Probe PRP at PRP atSize Perimeter Center Ratio Example - Sample (mm) (g) (g) of PRPCalpol ® - Sample 1 2 1917.5 3486.1 0.55:1 Calpol ® - Sample 2 2 2486.92874.7 0.87:1 Nurofen ® - Sample 1 2 596.8 1174.0 0.51:1 Nurofen ® -Sample 2 2 531.7 1060.8 0.50:1 Nurofen ® - Sample 3 2 639.4 1288.60.50:1 Nurofen ® - Sample 4 2 578.5 1174.5 0.49:1 Nurofen ® - Sample 5 2531.7 1060.8 0.50:1 Nurofen ® - Sample 6 2 639.4 1288.6 0.50:1Migranin ® 2 n/a >5000 n/a Alavert ® - Sample 1 1 1469.9 1370.9 1.07:1Alavert ® - Sample 2 1 1190.0 1390.2 0.86:1 Alavert ® - Sample 3 11270.1 1473.3 0.86:1 Claritin RediTab ® - Sample 1 1 244.4 271.7 0.90:1Claritin RediTab ® - Sample 2 1 296.2 529.7 0.56:1 Claritin RediTab ® -Sample 3 2 422.4 569.4 0.74:1 Claritin RediTab ® - Sample 4 2 605.4716.7 0.84:1 Imodium Instant Melts ® - 1 193.3 552.1 0.35:1 Sample 1Imodium Instant Melts ® - 1 323.4 560.3 0.58:1 Sample 2 Imodium InstantMelts ® - 2 346.4 693.3 0.50:1 Sample 3 Imodium Instant Melts ® - 2489.6 644.1 0.76:1 Sample 4 Minimum¹ 61.3 13.0 0.35:1 Maximum 659.7327.7 1.07:1

As is shown above, the samples of Examples 12 and 13 had a range of theratio of PRP of from 1.3:1 to 18.6:1, while the comparative orallydisintegrating products had a range of the ratio of PRP of from 0.35 to1.07:1

It is understood that while the invention has been described inconjunction with the detailed description thereof, that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the claims.

What is claimed is:
 1. A machine for the production of a solid dosageform, said machine comprising: (a) a die platen having one or moreforming cavities each having an inner wall, a first opening at thesurface of one side of said die platen, and a second opening at thesurface on the opposite side of said die platen; (b) one or more firstforming tools having a dosage form contacting first surface, each ofsaid one or more first forming tools adapted to move into one of saidcavities through the first opening of said forming cavity; (c) one ormore second forming tools having a dosage form contacting secondsurface, each of said one or more second forming tools adapted to moveinto one of said cavities through the second opening of said formingcavity; (d) at least one first RF electrode operably associated withsaid one or more first forming tools, said one or more second formingtools, or said inner wall of said one or more forming cavities; and (e)at least one second RF electrode operably associated with said one ormore first forming tools, said one or more second forming tools, or saidinner wall of said one or more forming cavities; wherein at least aportion of said dosage form contacting first surface and/or at least aportion of said dosage form contacting second surface is movable,respectively, within said first forming tool and/or within said secondforming tool, and wherein said machine is adapted to form a dosage formbetween said dosage form contacting first surface and said dosage formcontacting second surface within a forming cavity and wherein said firstRF electrode and said second RF electrode are arranged within saidmachine such that when RF energy is conducted between said first RFelectrode and said second RF electrode, said RF energy passes throughthe portion of said forming cavity adapted to form said dosage form. 2.A machine of claim 1, wherein said first forming tool comprises a firstvoid adapted to permit said moveable portion of said dosage formcontacting first surface to move within said first forming tool and/orsaid second forming tool comprises a second void adapted to permit saidmoveable portion of said dosage form contacting second surface to movewithin said second forming tool.
 3. A machine of claim 1, wherein saidmachine further comprises an RF energy source in communication with saidfirst RF electrode and said second RF electrode.
 4. A machine of claim1, wherein said first RF electrode is operably associated with said oneor more first forming tools, said second RF electrode is operablyassociated with said one or more second forming tools, and the portionof the inner wall of said forming cavity which is adapted to form saiddosage form is insulative to said RF energy.
 5. A machine of claim 3,wherein only a portion of the surface of said first forming tool that isadapted to contact said dosage form is operably associated with saidfirst RF electrode.
 6. A machine of claim 1, wherein said first RFelectrode is operably associated with said one or more first formingtools and second RF electrode is operably associated with the portion ofsaid inner wall of said one or more forming cavities that is adapted toform said dosage form.
 7. A machine of claim 1, wherein said first RFelectrode is operably associated with a first portion of said inner wallof said one or more forming cavities that is adapted to form said dosageform and second RF electrode is operably associated with a secondportion of said inner wall of said one or more forming cavities that isadapted to form said dosage form.
 8. A machine of claim 2, wherein saidmachine further comprises an RF energy source in communication with saidfirst RF electrode and said second RF electrode.
 9. A machine of claim2, wherein said first RF electrode is operably associated with said oneor more first forming tools, said second RF electrode is operablyassociated with said one or more second forming tools, and the portionof the inner wall of said forming cavity which is adapted to form saiddosage form is insulative to said RF energy.
 10. A machine of claim 3,wherein said first RF electrode is operably associated with said one ormore first forming tools, said second RF electrode is operablyassociated with said one or more second forming tools, and the portionof the inner wall of said forming cavity which is adapted to form saiddosage form is insulative to said RF energy.
 11. A machine of claim 8,wherein said first RF electrode is operably associated with said one ormore first forming tools, said second RF electrode is operablyassociated with said one or more second forming tools, and the portionof the inner wall of said forming cavity which is adapted to form saiddosage form is insulative to said RF energy.
 12. A machine of claim 1,wherein only a portion of the surface of said first forming tool that isadapted to contact said dosage form is operably associated with saidfirst RF electrode.
 13. A machine of claim 2, wherein only a portion ofthe surface of said first forming tool that is adapted to contact saiddosage form is operably associated with said first RF electrode.
 14. Amachine of claim 4, wherein only a portion of the surface of said firstforming tool that is adapted to contact said dosage form is operablyassociated with said first RF electrode.
 15. A machine of claim 8,wherein only a portion of the surface of said first forming tool that isadapted to contact said dosage form is operably associated with saidfirst RF electrode.
 16. A machine of claim 9, wherein only a portion ofthe surface of said first forming tool that is adapted to contact saiddosage form is operably associated with said first RF electrode.
 17. Amachine of claim 10, wherein only a portion of the surface of said firstforming tool that is adapted to contact said dosage form is operablyassociated with said first RF electrode.
 18. A machine of claim 11,wherein only a portion of the surface of said first forming tool that isadapted to contact said dosage form is operably associated with saidfirst RF electrode.
 19. A machine of claim 2, wherein said first RFelectrode is operably associated with said one or more first formingtools and second RF electrode is operably associated with the portion ofsaid inner wall of said one or more forming cavities that is adapted toform said dosage form.
 20. A machine of claim 2, wherein said first RFelectrode is operably associated with a first portion of said inner wallof said one or more forming cavities that is adapted to form said dosageform and second RF electrode is operably associated with a secondportion of said inner wall of said one or more forming cavities that isadapted to form said dosage form.